Acute Lung Injury & Acute Respiratory Distress Syndrome

Journal of Anesthesia & Critical Care: Open Access

Review Article Open Access Acute lung injury & acute respiratory distress syndrome - part I

Summary Volume 3 Issue 5 - 2015

NSAIDs are commonly used as single analgesics in minor surgery or as component of Fadhil Zwer multimodal analgesia associated with opioids or locoregional techniques in the postoperative Consultant Intensive Care Medicine at Private practice clinic, period to assure a better analgesia and reduce the dose of opioids. The analgesic potency Iraq evaluated as number needed to treat (NNT) is not very different between the traditional non selective NSAIDs and the selective cyclo-oxygenase-2-inhibitors (Coxibs). The Correspondence: Fadhil Zwer, Consultant Intensive Care effectiveness as analgesics is unquestionable also if these drugs are not devoid of risks. Medicine at Private practice clinic, Iraq, There is debate in literature about the possible side effects when administered in the Email perioperative period: anastomotic leakage, reduced ossification, bleeding and acute renal failure. Recent data underline as the Coxibs but also traditional NSAIDs can induce cardiac Received: August 28, 2015 | Published: November 26, 2015 toxicity even if they are utilized for few days. The aim of this review is to provide an overview of the effectiveness and side effects of selective and non-selective NSAIDs in the perioperative period.

History condition rapidly became recognized as one of the most challenging acute clinical processes to treat. Since acute, diffuse, and dense There are many interesting historical medical events that correlated bilateral infiltrates were almost never observed except in patients with or impacted the identification and management of ARDS requiring prolonged mechanical ventilation, many surmised the cause leading to the most new modern current concepts. These important of such infiltrates was the ventilator, hence the term [respirator lung]. and dramatic events set the stage for the critical care revolution that occurred in the last half of the twentieth century (Table 1).1 For a period of time ARDS had taken the name of inciting injuries (e.g., DaNang lung, shock lung, post-traumatic lung, etc.). It wasn’t In 1821, in what was probably the first published scientific until 1967, in a landmark article published in Lancet, that Ashbaugh, description, Laennec described the gross pathology of the heart and Bigelow, Petty, and Levine2 first described the clinical entity that they lungs and described the idiopathic changes of the lungs; pulmonary called [acute respiratory distress in adults]. This article recognized for Edema without heart failure in [A Treatise on Diseases of the Chest]. the first time that ARDS was a disarrangement of pathophysiologic By the 1950s, pulmonary edema had abnormalities common to 10 a relatively large number of patients but that were initiated by a wide variety of unrelated insults for example, gastric aspiration, sepsis, blunt trauma, near-drowning, etc. Interestingly, the difficulty in making the diagnosis remained evident in that at least five of the patients studied could have had ARDS secondary to or complicated by fluid overload. Also notable in this 1967 report, ARDS was acute respiratory distress syndrome. However, in 1971 Petty and Ashbaugh used the term adult respiratory distress syndrome in another publication probably to address the perception of ARDS as an adult version of the previously described infant respiratory distress syndrome (IRDS). The ARDS term firstly used as an adult respiratory distress syndrome but with more advances in researches and with more clarity of the syndrome which make diagnosis of the syndrome more accurate, it was found that this disorder may attacks not only the adult patients but even the children, so the term was changed from adult to acute respiratory distress syndrome. In 1992 the American European Consensus Conference (AECC) become a medical subject heading by the National Library of was charged with developing a standardized definition for ARDS Medicine; however, no distinction was made at that time between to assist with clinical and epidemiologic research. The AECC cardiac and non cardiac causes. Nonetheless, what evidently moved recommended that a new designation, acute lung injury (ALI), be ARDS from a nearly universally fatal form of double pneumonia was defined as a syndrome of inflammation and increased permeability that the development of methods of establishing secure airway access is associated with a changes of clinical, radiologic, and physiologic using tubes that could be attached to mechanical ventilators to deliver abnormalities that cannot be explained by, but may coexist with, left adequate pulmonary distending pressures. These techniques extended atrial or pulmonary capillary hypertension and is associated most often the lives of patients from a few hours to many days or even weeks, that with sepsis syndrome, aspiration, primary pneumonia, or multiple is a long enough to recover in some cases. As this new kind of patient trauma and less commonly with cardiopulmonary bypass, multiple began to populate the newly established intensive care units, their transfusions, fat embolism, pancreatitis, and others. Acute (not

Submit Manuscript | http://medcraveonline.com J Anesth Crit Care Open Access. 2015;3(5):14‒12. 1 ©2015 Zwer. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestrited use, distribution, and build upon your work non-commercially. Copyright: Acute lung injury & acute respiratory distress syndrome - part I ©2015 Zwer 2 adult) respiratory distress syndrome was defined as a subset of ALI of corticosteroids required a measured pulmonary wedge pressure patients with more severe oxygenation defect (more hypoxemia). ALI less than 19 mmHg. This once nearly routine measurement is now and ARDS are acute in onset and persistent, associated with one or much less frequent with the realization that exceeding an arbitrary more known risk factors, and are characterized by arterial hypoxemia pulmonary artery occlusion pressures (PAOP) does not exclude the resistant to oxygen therapy alone and diffuse radiologic infiltrates. diagnosis of ALI, and that there are usually other clinical data and In the decade of the 1970s ARDS became increasingly recognized, historical clues that allow a fairly secure diagnosis of ALI apart from but hydrostatic causes (e.g., volume overload) were difficult to rule volume overload to be made. Even when the PAOP is less than18 out. The potential for confusion was so great that measurements of mm Hg, one cannot be certain that edema is the result of altered pulmonary artery wedge pressure became a very common means of permeability. diagnosis. In fact, entry criteria for one of the earliest randomized trials Table 1 Medical events that made modern critical care possible1

Year Event 1896 Roentgen describes X-rays. Early chest X-rays required exposure time of 20 min and were not considered useful until the 1920s. 1929 Drinker and Shaw announce the invention of the iron lung during the polio epidemic. Fenn and coworkers publish work on pulmonary gas exchange, relating PO2, PCO2, respiratory exchange ratio, arterial O2 1946 saturation, alveolar ventilation, and altitude. 1950 Cortisone, first extracted in 1936, is used as a treatment for asthma. 1954 Clark develops an electrode for measurement of PO2, reflecting the level of O2 in the blood. 1954 Ibsen first used cuffed entdotracheal tubes and positive pressure ventilation. Forssmann and colleagues share the Nobel Prize in physiology and medicine for the advancement of right-heart catherization. Their 1956 work led to the development of the Swan Ganz catheter. Avery and Mead discover that some newborns’ lungs do not produce surfactant (hyaline membrane disease, later called neonatal 1959 respiratory distress syndrome). 1960 Moss and coworkers discover the benefits of chest compression to achieve artificial circulation. 1967 Ashbaugh and colleagues identify acute respiratory distress syndrome. 1960s First developed in the 1950s, it was the late 1960s before intensive care units become common in the United States. Extracorporeal membrane oxygenation (ECMO) is introduced for neonates with persistent pulmonary hypertension, allowing the 1976 lungs time to heal. Furchgott describes “endothelium-derived relaxing factor,” now known as nitric oxide. He was awarded the Nobel Prize for this 1978 work. Table 2 Definitions of the Acute Respiratory Distress Syndrome

Study No of Patients Patients PaO2/FiO2 Ratio Mortality Hospital mortality Lung open vent. Control 41-106 50 58 Meade 2008 983 ˃ 106-142 39 43 ˃ 142-180 33 33 ˃ 180-250 25 26 Hospital mortality <112 47 Villar 2011 220 112-142 30 >142 23 Hospital mortality ≤ 100 50 Cooke 2008 1113 ≤ 100 + shock 58 ≤ 100 + oliguric renal failure 71 ICU mortality Hospital mortality ˂ 112 45 45 Villar 2007 170 112-142 20 20 >142 6.3 12.6 Hospital mortality Rubenfeld 2005 1113 ˂ 200 (ARDS) 41.1 200-3000 (ALI) 38.5 ALI progressed to ARDS on day 3 or day 7 41 ALI no progression to ARDS on day 3 or day 7 28.6 ICU mortality Hospital mortality Brun-Buisson ALIVE study 2004 463 ˂ 200 (ARDS) 49.4 57.9 200-300 (ALI) 22.6 32.7 ICU mortality ˂ 100 83 100-149 47 Esteban 2002 120 150-199 31 200-300 25 >300 24 ICU mortality Hospital mortality Taccone Prone-Supine II 2009 342 ˂ 100 (sever ARDS) 42 50.7 100-200 (ARDS) 24 31.8

Table 3 Severity of hypoxemia and outcome in ALI/ARDS3

Part 1 Acute or chronic, depending on course. Part 2 Severity of physiological lung injury as determined by the lung injury score (see table 1-5). Part 3 Lung injury caused by or associated with known risk factor for ARDS such as sepsis, pneumonia, aspiration, or major trauma. Table 4 Three part expanded definition of clinical acute lung injury (ALI) and the acute respiratory distress syndrome (ARDS) proposed by Murray and colleagues6

Clinical Data Score No alveolar consolidation 0 Alveolar consolidation confined to 1 quadrant 1 Chest radiography Alveolar consolidation confined to 2 quadrants 2 Alveolar consolidation confined to 3 quadrants 3 Alveolar consolidation confined to 4 quadrants 4

PaO2/FiO2 ≥ 3000 0

PaO2/FiO2 225-299 1

Hypoxemia score PaO2/FiO2 175-224 2

PaO2/FiO2 100-174 3

PaO2/FiO2 ˂ 100 4

≤ 5cm H2O 0

6-8cm H2O 1

PEEP score (when mechanically vent.) 9-11cm H2O 2

12-14cm H2O 3

≥ 15cm H2O 4

≥ 80ml/cm H2O 0

60-79ml/cm H2O 1

Respiratory system compliance score (when available) 40-59ml/cm H2O 2

20-39ml/cm H2O 3

≤ 19ml/cm H2O 4 Table 5 Calculation of the lung injury score6

Criteria Timing Oxygenation Chest radiograph Pulmonary artery wedge pressure PaO /FiO ≤ 300 mmHg Bilateral infiltrates seen on frontal chest≤ 18 mmHg when measured or no clinical ALI criteria Acute onset 2 2 (regardless of PEEP level) radiograph evidence of left atrial hypertension PaO /FiO ≤ 200 mmHg Bilateral infiltrates seen on frontal chest≤ 18 mmHg when measured or no clinical ARDS criteria Acute onset 2 2 (regardless of PEEP level) radiograph chest radiograph evidence of left atrial hypertension The score is calculated by adding the sum of each component and dividing by the number of components used No lung injury – 0 Mild to moderate lung injury - 0.1-2.5 Sever lung injury (ARDS) - ˃2.5

Table 6 Recommended Criteria for Acute Lung Injury and Acute Respiratory Distress Syndrome21

PEEP ≤ 5 5 ˂ PEEP≤ 10 11≥PEP Total**

PaO2/FiO2˃175 23.1±5% 22.0±6% 25.9 ± 18% 23.1±2%

110˂ PaO2/FiO2≤175 31.4±9% 25.4±5% 28.1 ± 13% 27.8±3%

PaO2/FiO2≤ 115 35.7±2% 35.2±7% 38.2 ± 7% 36.5±3% Total * 27.8±3% 27.8±2% 33.3 ± 4%

6 Table 7 Mortality rates according to PaO2/FiO2 tertiles and PEEP levels

Defining Characteristic Operational Definition

1 Hypoxemia PaO2/FiO2˂200 mmHg with PEEP ≥10. 2 Acute onset Rapid onset in ˂72 hours. 3 Radiographic abnormalities Bilateral airspace disease involving ≥2 quadrants on frontal chest x ray. 4 Non cardiogenic in origin No clinical evidence of congestive heart failure (including use of pulmonary artery catheter and/or echo if clinically indicated). Static respiratory system compliance ˂50ml/cm H O (with patient sedated, tidal volume of 8 ml/kg, ideal body weight, PEEP ≥ 5 Decreased lung compliance 2 10). 6 Predisposition Direct and/or indirect factor associated with lung injury. -Overall mortality was 29.2% ± values are standard errors. Data analyzed using Cochran-Armitage trend test.

* Within each PEEP range there is a highly significant increase in mortality with lower PaO2/FiO2 levels (p ˂ 0.0001).

** Within each PaO2/FiO2 tertile there is no significant difference in mortality with increasing PEEP level.

Table 8 The Delphi definition of ARDS21

Acute Respiratory Distress Syndrome Timing Within 1 week of a known clinical insult or new worsening respiratory symptoms. Chest imaging* Bilateral opacities – not fully explained by effusion, lobar/lung collapse or nodules. Respiratory failure not fully explained by cardiac failure or fluid overload need objective Origin of Edema assessment (e.g. echogradiography) to exclude hydrostatic Edema if no risk factor present.

Mild 200 mmHg˂PaO2/FiO2≤300mmHg with PEEP or CPA≥5cm H2O*** Oxygenation** 100mmHg˂ PaO /FiO ≤ 200 mmHg with PEEP≥5cmH O. Moderate Severe 2 2 2 PaO2/FiO2≤100 mmHg with PEEP ≥5cmH2O. ARDS is indicated by the presence 1 of criteria -4 and one of 5 or 6. Table 9 The Berlin definition of ARDS (the ARDS definition task force: the Draft Berlin Definition, ESICM 24 the Annual Congress Berlin, October 2011)

ARDS severity PaO2/FiO2 * Mortality ** Mild 200 – 300 27% Moderate 100 – 200 32% Sever ˂ 100 45% * = chest radiograph or CTscan.

** = if altitude is higher than 1000 m, the correction factor should be calculated as follow: [PaO2/FiO2× (barometric pressure/760)]. *** = this may be delivered non-invasively in the mild acute respiratory distress syndrome group. Table 10 Berline definition of ARDS and mortality rate22

Pulmonary ARDS Extrapulmonary ARDS Bacterial, fungal, viral and parasitic pneumonia. Sepsis. Aspiration of gastric content. Trauma. Pulmonary contusion. Drug overdose. Inhalation injury. Acute pancreatitis. Fat emboli. Cardiopulmonary bypass. *= on PEEP 5+ **= observed in cohort. Table 11 Underlying etiologies of pulmonary and extrapulmonary acute respiratory distress syndrome19

Pulmonary ARDS Extrapulmonary ARDS Alveolar epithelium ↑↑ damage Damage Altered type I and II cell ↑↑ damage Normal Alveolar neutrophils Prevalent Rare Alveoli Apoptotic neutrophils Prevalent Rare Fibrinous exudate Present Rare Alveolar collapse ↑↑ increased Increased Local interleukin Prevalent Rare Interstitial edema Absent High Collagen fibers ↑↑ increased Increased Interstitial space Elastic fibers Normal Normal Capillary endothelium Normal ↑↑ damage Interleukin Increased ↑↑ increased Blood TNF-α Increased ↑↑ increased Table 12 Histological and biochemical alterations in pulmonary and extrapulmonary acute respiratory distress syndrome19

Exposure Frequency Discordant pairs* Concordant pairs* Variables Recurrent ALI% Single ALI% +/ ̶ ̶/+ +/+ ̶/ ̶ Gastro-esophageal reflex disease 79 26 11 1 4 3 Proton pump inhibitors use 42 16 6 1 2 10 H2 blocker use 32 11 5 1 1 12 Aspiration of gastric contents 37 16 5 1 2 11 Chronic pain 5 0 1 0 0 18 Chronic opioid use 21 0 4 0 0 15 Smoking 68 47 8 4 5 2 Chronic alcohol use 10 10 2 2 0 15 Obstructive lung disease 31.6 21.1 4 2 2 11 Immunocompromised 10.5 5.3 2 1 0 16 Diabetes mellitus 31.6 15.7 5 2 1 11 Body mass index (BMI) ≥ 30 31.6 4 5 3 1 10 Transfusion 26 32 3 4 2 10

Reduced colloid oncotic pressure as observed in hypo albuminemic for more than 24 hours met established criteria for ARDS. A European states promotes edema in the absence of permeability changes. Lung survey of 132 intensive care units similarly demonstrated that 18% dysfunction secondary to direct insults to the lung, for example, of mechanically ventilated patients mostly had ARDS. Because aspiration (primary ARDS), may be different from lung injury from ALI/ARDS is a syndrome and not a disease, patients are defined as extra pulmonary origin, for example, sepsis (secondary ARDS). This having ALI/ARDS when they meet predetermined diagnostic criteria. is an interesting concept, and some clinical markers that differentiate Potential goals for these diagnostic criteria are to identify patients the two have been described. However, work is still underway to with a specific clinical entity for epidemiological purposes and to determine implications for patient management. The differential select patients who will respond to ALI/ARDS specific therapies. The diagnosis of ARDS using the AECC definition, is significantly broad diagnostic criteria used to define ALI/ARDS have progressed over that the resulting list of other potential confusing diagnoses is limited time. to diseases that appear similar with regard to chest radiography For the purpose of clearing an essential one of criteria [which will and oxygenation defect, but are sub acute or chronic: interstitial or mention frequently in the discussion] for definition of ALI/ARDS, so idiopathic pulmonary fibrosis, lymphangitic carcinoma, pulmonary the abbreviation of PaO /FiO must be clarified (see the box bellow). veno occlusive disease; or are due to increased hydrostatic pressures: 2 2 A PaO /FiO ratio is an index to characterize the ALI/ARDS, which mitral stenosis, left ventricular failure, intravascular volume overload. 2 2 involves severe hypoxemia (insufficient oxygen content in blood). Thus the diagnosis of ARDS is inclusive and indeed can coexist with PaO is the partial pressure of oxygen in arterial blood. It’s usually other more specific diagnoses such as pneumococcal pneumonia. 2 measured in millimeters of mercury (mmHg or Torr) by the test

As mentioned above, the first description of acute respiratory called arterial blood gas (ABG) analysis. PaO2 of 75 to 100 mmHg is 2 distress syndrome appeared in 1967, in a paper by Ashbaugh et al. considered normal. FiO2 is the fraction of inspired oxygen or, simply which described 12 patients with acute respiratory distress, cyanosis percentage of oxygen, in a gas mixture atmospheric or given by refractory to oxygen therapy, decrease lung compliance, and diffuse medical gas equipments. For example, the atmospheric air has FiO2 of infiltrates on chest radiography. In 1988, an expanded definition 21% (0.21). If a patient needs mechanical ventilation, FiO2 is usually was proposed based on the level of positive end-expiratory pressure in the 30-to-40% range. Therefore, the normal ratios in condition of (PEEP), the ratio of the partial pressure of arterial oxygen to the patient inhaling spontaneously [atmospheric air] without incremental fraction of inspired oxygen, the static lung compliance, and the degree oxygen will be: of infiltration evident on chest radiography. Another measurement, the PaO /FiO =75/0.21=357 [lower acceptable ratio] lung injury score, has been widely used to quantify the disease severity 2 2 in clinical trials, although it has not been shown to accurately predict 85/0.21=404 outcome during the first 24 to 72 hours after the onset of ARDS. 95/0.21=452 In 1994, a new definition was recommended by the American- European Consensus Conference Committee (Table 2), which 100/0.21=476 [upper ratio] recognized the variability in severity of lung injury, and separated Although ALI/ARDS are syndromes caused by different injuries patients into two groups: those with less severe hypoxemia were and conditions, the patho-biology of the lung injury and similar clinical categorized as having acute lung injury and those with more severe picture makes an obligating state for us to study them as a single entity hypoxemia were defined as having ARDS. However, factors such as rather than characterize the individual risk factors as separate clinical the underlying cause and involvement of other organ systems are not entities. More importantly an array of potential specific targets for a part of the existing definition (Table 2). pharmacologic intervention can be applied to ALI/ARDS as a disease entity as a whole. The clinical presentations consistent with ALI Abbreviations: IRDS, infant respiratory distress syndrome; and ARDS can arise in patients of all ages from direct (pulmonary) AECC, american european consensus conference; ALI: acute or indirect (extra pulmonary) insults that induce pulmonary lung injury; PAOP: pulmonary artery occlusion pressures; PEEP, inflammation, damage the cells of the alveolar-capillary membrane, positive end-expiratory pressure; ABG, arterial blood gas; LIS, lung and lead to severe acute respiratory failure. Uniform diagnostic injury score; AECC, american-european consensus conference; OI, criteria are essential for meaningful clinical studies and therapeutic oxygenation index; MAP, mean airway pressure; ATS, american development for ALI/ARDS. The clinical entities of ALI and ARDS thoracic society; SCCM, society of critical care medicine; TNF, are syndromes defined by a relatively limited set of descriptive patho- tumor necrosis factor; BAL, broncho alveolar Lavage; CT, computed physiologic clinical findings, and patients are included regardless tomography; APACHE, acute physiology and chronic health of the specific etiology of acute pulmonary dysfunction. Although a evaluation; LIPS, lung injury prediction score working definition of ALI/ARDS that includes both pulmonary and Definitions of ALI/ARDS extra pulmonary causes can have benefit in standardizing supportive intensive care, it can also complicate assessments of the efficacy The acute lung injury and acute respiratory distress syndrome of therapeutic interventions. For example, the lack of stratification are characterized by increased permeability of the alveolar- of patients with ALI/ARDS by etiologic causes has the potential to capillary membrane, diffuse alveolar damage, the accumulation of confound Data interpretation in therapeutic trials, since interventions proteinaceous interstitial and intra-alveolar edema, and the presence that might benefit one cause of ALI/ARDS may have no benefit or of hyaline membranes. These pathological changes are accompanied may even be harmful in treating another etiology. by physiological alterations including severe hypoxemia, an increase Anyhow, there exist major differences in the pathogenesis of these in the mean pulmonary dead-space fraction, and a decrease in individual insults especially when studied in animal model systems. pulmonary compliance. ARDS is a relatively common diagnosis in However, there are major advantages of defining a syndrome like patients who require mechanical ventilation for greater than 24 hours. ALI/ARDS: In a population based cohort study of 21 hospitals over a 16-month period of time, 21% of patients who required mechanical ventilation

1. A standardized universal definition for ALI/ARDS has many c. Exclude heart failure objectively (use of cardiac echocardiogram). benefits. Most importantly, it would allow comparison of the d. Only include patients with P/F ratio with standard ventilator findings of various clinical trials in ALI/ARDS with a greater settings of less than 2003 (Table 3). degree of certainty. For the clinician, a functional definition of ALI/ARDS allows early institution of standardized clinical The first official description of ARDS was reported in 1967 and care, i.e. certain therapeutic modalities that have been tested consisted of a case series of 12 patients with the acute onset of dyspnea, and proven to have benefits. For instance, early identification tachypnea, severe hypoxemia, chest radiographic abnormalities and of patients with ALI/ARDS allows the early application of decreased static respiratory system compliance.2 With the increased protective lung ventilation with lower tidal volumes based on availability of pulmonary artery catheterization in ICUs, ARDS predicted body weights. was recognized as a non-cardiogenic form of pulmonary edema, characterized by the accumulation of both protein and cells in the 2. Additionally, a standardized definition including ALI and alveoli in the presence of normal left atrial pressures. Subsequently, ARDS can assist with outcome prognostication and is of help several ARDS definitions were used in the early 1980s that required especially while discussing the care of the patient with families. at least four basic clinical features, three of which were based on For the researcher, it helps to capture a larger patient population physiological and radiographic criteria adapted from this original case for potential recruitment into large clinical studies, as proven series: by multiple clinical trials conducted under the observations of the ARDS network. Moreover, it offers a common language of a. Hypoxemia (varying severity). communication between the basic and clinical researcher where therapeutic modalities can be constantly tested in the laboratory b. Decreased respiratory system compliance. and brought to the clinical practice. c. Chest radiographic abnormalities (often of an ill-defined type 3. It has to be understood that while combining both ALI and and degree). ARDS as one entity offers advantages, the results of the clinical d. The fourth diagnostic criterion was usually the documentation of studies with testing of therapeutic modalities have to be carefully a pulmonary artery occlusion pressure of 18 mmHg or less using interpreted, as many specific discrete disease entities have been a pulmonary artery catheter. examined as one. When the mortality associated with ARDS did not appear The traditional thinking with ARDS is that it is the multi-organ to improve during the1980s, the possibility was raised that the dysfunction and not hypoxemia that is responsible for mortality. requirement of all four of these criteria biased the understanding of This was based on a number of ARDS network trials where hypoxia ARDS and contributed to the negative results of several therapeutic was well tolerated (up to saturations of 88%) and improvements in trials for ARDS. One concern was that these strict diagnostic criteria oxygenation did not lead to a survival advantage. It is important that required placement of a pulmonary artery catheter only identified to point out that some studies after the adoption of lung protective patients with severe ARDS and a very poor prognosis. The requirement strategies have suggested a strong correlation between the severity for pulmonary artery catheterization could also delay the diagnosis of 3 of hypoxemia and ICU or hospital mortality (Table 3). In light of ARDS [4]. Because approximately 50% of patients develop ARDS this, it is recommended that in future clinical trials of ALI/ARDS, within the first 24 hours of meeting an at-risk diagnosis, delaying the severity of hypoxemia should be considered upon patient enrollment administration of a therapy in order to insert a pulmonary artery catheter into the study, and that outcomes should be assessed based on severity may diminish the chance for a successful therapeutic intervention. of hypoxemia. What could be the reasons for these observations? One More recently, large clinical trials have demonstrated that a pulmonary can speculate on the following possibilities. In patients with severe artery catheter does not improve outcome for a variety of critically ill hypoxia, there is perhaps increased incidence of hyperoxia-induced patients including patients with ARDS. The older diagnostic criteria lung injury from increased requirements of FiO2 to maintain saturations of ARDS also lack specificity. For example, patients with vasculitis of 88%. Hyperoxia has been implicated as a factor responsible for and alveolar hemorrhage meet the diagnostic criteria for ARDS, yet increased lung injury in many animal models by the generation of the pathogenesis of this disorder is different from ARDS. In addition, reactive oxygen species, increased apoptosis and necrosis. In addition patients with an elevated pulmonary artery occlusion pressure are it is important to consider the patho-physiological disturbances linking excluded, although these patients may have lung injury in addition ARDS with multi-organ dysfunction. Is the multi-organ dysfunction to either hypervolemia or congestive heart failure (either systolic as a result of ALI/ARDS or is the ALI/ARDS a result of multi-organ or diastolic). Several investigators postulated that the differences dysfunction? Are these two separate entities? These questions need in reported epidemiological data, such as mortality rates, could be to be fully explored in additional studies through basic and clinical attributed to inconsistent cut off values for the hypoxemia criteria research. Anyhow, over the past few years many different study and variations in the interpretation of other diagnostic considerations. groups have raised doubts about the validity of the current ALI/ARDS The presentation of ARDS includes a continuum of radiographic and definitions and have recommended a change. It is strongly felling that arterial blood gas abnormalities, and any single cut off value for the it is time to change the definition after 17 years of the predominant use definition of ARDS is arbitrary. Therefore, the identification of several of the AECC definition for ALI/ARDS. Based on available data with gradations or categories of acute lung injury that have prognostic or various validity studies it is suggested that the new definition should therapeutic implications would be beneficial. be standardized as follows: The murray lung injury score: Over the next two decades the a. Risk factors-Direct (Pulmonary) or Indirect (Extra-pulmonary), basic definition was thought by many experts to be a hindrance to as most experimental data suggest that these two entities have understanding the syndrome. The definition was not sufficiently distinct pathogenic mechanisms. specific, was open to varying interpretations, and did not require the clinical etiology of the syndrome to be specified. Investigators b. Calculation of PaO2/FiO2 ratios with specific and standard ventilator settings (PEEP and MAP [mean airway pressure]). used different criteria to enrol patients in clinical studies making

The expanded definition had several advantages. By describing of PEEP, but PaO2/FiO2 then increased to greater than 200 or even whether patients had an acute course with rapid resolution or a more 300 when low to moderate levels of PEEP were subsequently applied. chronic course, the definition differentiated between the rapidly In these patients, atelectasis could have been an important cause resolving course typical of ARDS secondary to drug overdoses or of hypoxemia rather than shunt from consolidation and pulmonary pulmonary contusion and the complicated and protracted course of edema. In one study the mortality of these patients was considerably many patients with severe pneumonia or sepsis syndrome. The LIS lower than those whose PaO2/FiO2 remained below 200 after raising quantified the severity of lung injury separating patients with severe PEEP. Moreover, in many patients with bilateral infiltrates, PaO2/ lung injury (LIS >2.5) from those with mild lung injury (LIS<2.5– FiO2 increased substantially when FiO2 were raised from moderate >0.1). Most importantly, the identification of the cause or associated to high levels. This suggests that among patients with similar PaO2/ medical condition addressed the etiology of lung injury. As the authors FiO2, oxygenation failure is worse and risk of death is higher in those argued, [grouping all causes of ARDS under an umbrella classification receiving higher FiO2. Thus, without standardized or minimum PEEP potentially prevented the discovery of beneficial treatments aimed at and FiO2 criteria, the AECC criteria could identify a heterogeneous a particular cause.6 group of patients, some of whom are at low risk of adverse outcomes such as death. If so, then use of the AECC criteria to identify The American-european consensus conference patients for ALI/ARDS trials, without PEEP and FiO2 criteria, could [AECC]: Subsequently, the American-European Consensus reduce the power of clinical trials because potential effects of new Conference (AECC) on ARDS was convened with a major goal of interventions may besmaller in patients with mild disease. Some bringing uniformity to the definition of ARDS. The diagnostic criteria investigators have speculated that the results of trials that enrolled for ARDS proposed by this committee were PaO2/FiO2≤ 200, bilateral ALI/ARDS patients using the AECC criteria without a minimum infiltrates on chest radiograph that need not be diffuse, and pulmonary PEEP level were confounded by imbalances between study groups in artery occlusion pressure≤18 mmHg or no clinical evidence of left patients with mild and severe lung injury that could not be detected atrial hypertension when a pulmonary artery catheter was not used. without increasing PEEP.7 The National Institutes of Health ARDS The spectrum of disease severity was also expanded to include patients Network used the AECC criteria as the inclusion criteria for most of with milder hypoxemia. This definition, which includes patients with its clinical trials since 1996. Exclusion criteria reduced heterogeneity ARDS, was called acute lung injury (ALI), and the diagnostic criteria of the enrolled populations, but patients were not excluded if they were similar except the PaO /FiO ratio was ≤300 (Table 6). 2 2 were on zero or low PEEP or low FiO2 [8]. However, it was found To determine the accuracy of the Murray lung injury score that the baseline PEEP alone predicted mortality, but after controlling for baseline PaO /FiO , PEEP did not predict mortality (Table 7). In and the AECC definition, the diagnostic criteria for these two new 2 2 definitions were compared to the previous definition of ARDS that conclusion the consensus conference definitions differed from the required all four diagnostic criteria. Both definitions maintained a lung injury score in four areas: high degree of accuracy (˃90%) for those ICU patients with a clearly a. The AECC definition did not use a four point chest x ray scoring defined at-risk diagnosis for the development of ARDS. Therefore, it system and instead looked for the appearance of bilateral is likely that the lung injury score and the AECC definition actually infiltrates. identify a patient population similar to the older strict definitions of ARDS for those patients with clearly defined at-risk diagnoses. b. PEEP measurements were excluded in an effort to reduce The members of the AECC decided again to clarify some questions variability in utilization of PEEP by individual physicians. concerning their diagnostic criteria for ARDS. They acknowledged c. A different degree of hypoxemia was required for the oxygenation that the theoretical differentiation of ARDS from ALI based on criteria. severity of hypoxemia had not established two separate entities with different clinical associations and prognoses. In regard to the chest d. They included either measurements of pulmonary artery radiographic criteria, the committee stated that the bilateral infiltrates occlusion pressure or absence of clinical evidence of left atrial should be consistent with pulmonary edema, even if mild or patchy hypertension. in nature. Opacities that were not considered appropriate for the

Anyhow, both scores identified the same group of patients 0.577, compared to 0.536 for the old definition (Table 10). Clinical despite differing criteria used in the definitions. The addition of variables that are widely believed to be important and useful in the PEEP requirement as a criterion in the lung injury score did not alter management of ARDS – static compliance of the respiratory system, the sensitivity and specificity of the score, as shown previously by radiographic severity, PEEP˃10 and corrected expired volume ˃10L/ Moss [9]. The use of PEEP in restoring functional residual capacity min – were not predictive of mortality or other clinical outcomes. in patients with acute lung injury ALI/ARDS is well accepted. After including these variables in the initial draft definition and testing Almost really all patients had a four point score from the chest x ray them empirically in the cohort, they were all dropped from the final value in the lung injury score, which would approximate with the Berlin definition for ARDS (Table 10). chest radiograph finding of diffuse bilateral infiltrates in the AECC It is really the authors did find a post-hoc high risk profile of definition. All patients had a PaO /FiO of<175, thus fulfilling both 2 2 patient with 52% mortality from ARDS. These patients had sever definitions of ARDS. Considerable discussion has been centered on ARDS (PaO /FiO ratio˂100) and either a static compliance of ≤20ml/ the cut off between ALI and ARDS with regard to the PaO /FiO with 2 2 2 2 cmH O or a corrected expired volume of ≥13 L/min. What was wrong many suggesting a cut off value of < 150 rather than < 200. Concerns 2 with old definition of ARDS: were that the more liberal definitions might include non-ARDS related illnesses with altered gas exchange.10 a. Acute onset of hypoxemia with PaO2/FiO2 ratio ≤ 200mmHg. The Delphi definition of ARDS: In 2005, Ferguson and colleagues b. Bilateral infiltrates on chest x ray. used a formal consensus-building process called the Delphi technique in an attempt to further improve upon the accuracy of the AECC c. No evidence of left atrial hypertension. definition of ARDS. The goal of this process was to reduce bias In addition: and improve the operating characteristics of the selected diagnostic criteria. A group of 11 opinion leaders first identified several defining a. No clear criteria for defining acute – leading to ambiguity characteristics of ARDS, and then refined and reduced these criteria regarding cases of acuteon- chronic hypoxemia. through a pooled and anonymous feedback system. The end result b. High inter observer variability in interpreting chest x rays. were slightly different diagnostic criteria from the AECC definition c. Difficulties identifying/ruling out cardiogenic or hydrostatic including a definition of hypoxemia that required a PaO2/FiO2 ratio of ≤200mmHg with a PEEP of ≥10, the documentation of a predisposing pulmonary edema especially in an era of using pulmonary artery risk factor for the development of ARDS, and the reinsertion of a catheter. decreased static respiratory system compliance (Table 8). d. PaO2/FiO2 ratio is sensitive to changes in ventilator settings. Oxygenation index (OI) and PaO /FiO ratio: Oxygenation Index 2 2 The panel’s findings sported by the European Society of Intensive (OI) is the most widely used system to quantify the degree of lung Care Medicine, the American Thoracic Society (ATS) and the Society injury and hypoxemia in pediatric critical care. OI specifically takes of Critical Care Medicine (SCCM) emerged from meetings in Berlin into account mean airway pressure (MAP), an important determinant to try to address the limitations of the earlier AECC definition.12 of oxygenation. OI is defined as the product of MAP× FiO2×100/

PaO2. OI has been associated with outcome in both adults and children Relationship between definitions: Several studies have examined with ALI/ARDS. The original study in 2005 reported on the ability of the relationship between the definition of ARDS proposed by Murray OI to predict the duration of mechanical ventilation but not survival. et al and that of the NAECC. A prospective trial using strict diagnostic Since then many adult studies have examined the efficacy of OI as a criteria for ARDS as the gold standard evaluated the diagnostic predictor of both duration of mechanical ventilation and mortality. In accuracy of the LIS, the NAECC definition, and a modified LIS in comparison, measurement of PaO2/FiO2 as a predictor of mortality identifying patients with ARDS. The modified LIS consisted of two in ALI/ARDS is uncertain. Although there are little differences in components: a PaO2/FiO2 of ≤174 (corresponding to grade 3 or higher outcome based on PaO2/FiO2 ratio early in the course of ARDS, it LIS (Table 5)) and bilateral infiltrates on a chest radiograph. The is likely that persistently lower PaO2/FiO2 ratios are associated with following diagnostic criteria for ARDS served as the gold standard: higher mortality. concomitant presence of respiratory failure requiring mechanical ventilation; bilateral pulmonary infiltrates; PaO /PAO2<0.2; The Berlin definition: A proposal for an update of the AECC ARDS 2 PAOP<18mmHg; and static respiratory system compliance <50ml/ definition has been published recently by a task force panel of experts cm H O. 123 patients with at least one of seven at risk diagnoses were using a similar terminology as had been previously reported (ARDS 2 followed prospectively for the development of ARDS. The diagnostic definition task 2012). Using teleconferencing, in-person discussions accuracy in the at risk population (true positive + true negative/total and retrospective data, they proposed an ARDS classification with number of patients) was 90% for the LIS definition and 97% for both three severity categories (mild, moderate, and severe) for empirical the modified LIS and the NAECC definitions. It is concluded that the evaluation. The term mild ARDS was used for defining those patients three scoring systems identified similar populations when applied to who are considered as ALI in the AECC definition (300≥ PaO / 2 patients with clearly defined at risk diagnoses. FiO2>200mmHg). The term moderate was used for patients with a

PaO2/FiO2>100mmHg but<200, and the term severe for those with A more recent study assessed the agreement between the a PaO2/FiO2≤100mmHg. The panel had found that hospital mortality definitions of Murray et al and the NAECC in diagnosing ARDS in increased with every stage of severity [progression from one category a prospective trial of 118 patients comparing ventilation strategies. to another is associated with increased mortality] (mild 27%, moderate The incidence using the LIS was 62% while that using the AECC 32%, severe 45%) (Table 9).11 definition was 55%. Statistical agreement between the two definitions was moderate and improved when analysis was limited to patients Although it is emphasized that the increased power of the new who had undergone compliance measurements (65%). A more liberal Berlin definition to predict mortality compared to the AECC PaO /FiO ratio decreased agreement, as did increasing the LIS definition, in truth it’s still poor, with an area under the curve of only 2 2 threshold diagnostic of ARDS to 3 or decreasing it to 2. Omitting

Citation: Zwer F. Acute lung injury & acute respiratory distress syndrome - part I. J Anesth Crit Care Open Access. 2015;3(5):11‒12. DOI: 10.15406/jaccoa.2015.03.00109 Copyright: Acute lung injury & acute respiratory distress syndrome - part I ©2015 Zwer 9 data on oxygenation, chest radiography, PAOP, PEEP, or respiratory if they had diffuse alveolar damage defined as the presence of hyaline compliance either decreased agreement or left it unchanged. While membranes plus at least one of the following criteria: alveolar type I agreement between the definitions was only moderate, there was no or endothelial cell necrosis, edema, organizing interstitial fibrosis, or difference in mortality between the two groups of patients identified. prominent alveolar type II cell proliferation. A total of 127 (33%) of The authors concluded that, for investigative purposes, the two criteria the patients met the AECC diagnostic criteria, and 112 (29%) met the could be used interchangeably. pathological diagnosis. The sensitivity and specificity of the AECC definition using the pathological diagnosis as the gold standard was Significance of definitions in clinical trials: The AECC updated 75% and 84%, respectively. The accuracy of the AECC definition did its recommendations in 1998. Although no formal changes were not improve when only the 284 patients with risk factors were included. made, the Committee emphasized the importance of addressing The most common pathological findings in those patients who met the epidemiological and etiological differences between patients when AECC criteria for ARDS but did not fulfill the pathological diagnosis designing clinical trials. Several prospective studies had identified of ARDS were pneumonia, pulmonary hemorrhage, and pulmonary risk factors present at the onset of lung injury that predicted poorer edema. Conversely, the clinical diagnoses of the patients who met the outcomes; clinical trial organizers would need to ensure an equal pathological criteria for ARDS but did not meet the AECC clinical distribution of these risk factors in their experimental and control criteria were again pneumonia and pulmonary edema. A Brazilian arms. They also encouraged further research focused on identifying study examining the results of only22 autopsy studies again confirmed markers predictive of progression to or poor outcomes from lung the relative inaccuracy of the AECC definition.13 Studying a subset of injury. Previous definitions had relied on abnormalities of lung 138 patients from the previously cited Esteban data, the diagnostic physiology to grade injury; however, neither the initial LIS nor the accuracy of the lung injury score and the recently developed Delphi initial PaO /FiO ratio was predictive of mortality in clinical trials. 2 2 definition were determined and compared to the AECC diagnostic Some biological markers, on the other hand, had already been proved criteria. Unfortunately, these two additional definitions of ARDS to be useful in identifying patients at risk for poor outcomes. For also did not accurately identify patients with pathological evidence example, raised levels of procollagen III peptide in early broncho of ARDS. The sensitivity for the diagnosis of ARDS was similar for alveolar lavage and pulmonary edema fluid samples predicted a all three definitions. However, the specificity of the lung injury score protracted clinical course with progression to pulmonary fibrosis in and the Delphi definition were significantly better than the AECC patients with ALI/ARDS, and increased levels of von Willebrand definition. factor antigen in plasma predicted the development of lung injury in patients with non pulmonary sepsis syndrome. Also, a recent study The chest radiographic criteria used to define ARDS also reported that higher levels of von Willebrand factor antigens in the remain problematic. When 21 established investigators reviewed 28 plasma of ALI/ARDS patients independently predicted mortality randomly selected chest radiographs from intubated patients with early in the clinical course. The importance of standard definitions a PaO2/FiO2 of ˂ 300, there was considerable variability in their and a mechanistic approach to enrolling patients in clinical trials are interpretations of whether the films were consistent with ARDS. apparent in the results of two recent randomized multicentre trials. Other studies have also demonstrated a similar lack of consistency The first, conducted by the ARDS Network, evaluated the benefits of in chest radiographs scores when using the four-point radiographic a low tidal volume strategy of mechanical ventilation and found an criteria from the Murray lung injury score. However, formal training absolute reduction in the primary outcome of death prior to hospital in the interpretation of chest radiographs for the diagnosis of ARDS discharge of 9% using lower tidal volumes (22% relative reduction can improve the inter-rater reliability between investigators. After a in mortality). Patients were enrolled using the 1994 definition and standardized session during which physicians refined the standards the benefit of a protective ventilation strategy was maintained in all and rules they would apply to the radiographic interpretation, their subsets of patients with ALI/ARDS. inter-rater reliability in regard to identification of chest radiographs consistent with ARDS was nearly perfect. Therefore, formal training The importance of identifying the mechanism of lung injury is in radiographic interpretation among investigators would decrease the borne out by a recent trial of recombinant human activated protein heterogeneity of patients enrolled in clinical trials for ARDS. There is C in severe sepsis. A 96 hour infusion of protein C resulted in an also controversy surrounding the specific hypoxemia criteria included absolute reduction in mortality of 6.1% (20% relative reduction) in the definition of ARDS. Individual or institutional variations in in a large international multicentre trial; 54% of the 1690 patients mechanical ventilator strategy could impact the incidence of ARDS/ had a pulmonary source of sepsis and 75% required mechanical ALI in an ICU or medical center. Increasing the level of PEEP alone ventilation on entry into the study. Although the study did not report may improve the PaO and directly alter the PaO /FiO ratio. Several the number of patients who met the criteria for ALI/ARDS, it is likely 2 2 2 studies have demonstrated that up to 50% of patients who meet the that most did since ARDS is the most common cause of respiratory hypoxemia criteria for ARDS without PEEP will significantly improve failure in sepsis and sepsis is the most common predisposing factor their oxygenation with higher levels of PEEP, and subsequently may for the development of ARDS. Based on this study, it is likely that no longer meet the hypoxemia criteria for ARDS. As a result, a PEEP a trial of protein C in patients with lung injury due to sepsis will requirement of 12 cm H O was included in the hypoxemia criteria show a treatment benefit while the same trial in patients with ARDS 2 in the Delphi definition in order to exclude these patients as being due to trauma or fat emboli may not. As more is learned about the diagnosed with ARDS. However, it is presently unclear what specific epidemiology and pathophysiology of ARDS, identifying the cause of level of PEEP should be included in the definition and whether the injury in designing treatment trials will become increasingly critical.6 inclusion of a PEEP requirement results in the identification of a Persistent problems and controversies involving the definition more homogeneous group of ARDS patients. Anyhow, in order to of ARDS: In spite of these several attempts to develop diagnostic differentiate ARDS from hydrostatic (cardiogenic/volume overload) criteria for ARDS, fundamental problems still remain. Esteban and pulmonary edema, the AECC consensus definition includes either colleagues determined the validity of the AECC diagnostic criteria a pulmonary artery occlusion pressure of ≤18mmHg or no clinical against autopsy results in 382 patients who died while in the ICU. evidence of left atrial hypertension. Some patients who meet clinical Patients were considered to fulfil the pathological diagnosis of ARDS criteria for ARDS may have a pulmonary capillary occlusion pressure

Citation: Zwer F. Acute lung injury & acute respiratory distress syndrome - part I. J Anesth Crit Care Open Access. 2015;3(5):11‒12. DOI: 10.15406/jaccoa.2015.03.00109 Copyright: Acute lung injury & acute respiratory distress syndrome - part I ©2015 Zwer 10 that is above the selected cut off value of 18 mmHg. In the ARDS as well as attempting to ignore the cardiogenic nature of the process. network pulmonary artery catheter trial, 29% of ALI patients had a With such great discrepancies, and in view of the fact that the lungs pulmonary artery occlusion pressures that exceeded the traditionally suffer diverse types of injuries related to various etiologies, it is not accepted threshold of 18 mmHg. In addition, there are no specific surprising that the lung injury diagnosis criteria are not accurate. recommendations by the AECC committee about what constitutes However, there is no simple solution for this problem, and this could clinical signs of an elevated left atrial pressure. Depending on explain the fact that the AECC criteria have continued to be used the specific diagnostic criteria used to define clinical left atrial since their implementation in 1994, despite the known limitations, to hypertension, between 5% and 30% of patients meeting chest clinically diagnose ARDS. For example, adding inflammatory markers radiograph and hypoxemia criteria may be excluded from a formal to the diagnosis in an attempt to include pathogenic data would not diagnosis of ARDS. Despite these concerns, the present diagnostic necessarily increase the accuracy, since there are many mediators criteria of the AECC definition have proven to be extremely useful involved and none are specific to the syndrome. In addition, invasive in regar to clinical trial design. Importantly, patients who meet the procedures such as bronchoalveolar lavage, which is not always present AECC definition of ARDS respond to specific therapies that easy to perform in critical patients, would be required to measure are associated with improvement of their outcome including a 25% the markers involved in the lung injury. The primary implication reduction in mortality with the use of a low tidal volume ventilatory of these results is that when there is a clinical suspicion of ARDS, strategy and a significant reduction in ventilator free days with the use other diagnostic hypotheses should be considered, whether associated of a fluid conservative strategy.1 with the syndrome or not. There is a diverse group of pulmonary parenchymal diseases with non infectious etiologies such as alveolar Accuracy of Clinical diagnosis of acute respiratory hemorrhage, pulmonary embolism, neoplasias, bronchiolitis distress syndrome obliterans organizing pneumonia, acute eosinophilic pneumonia and Using the AECC criteria, and consequently the accuracy drug toxicity that could have acute onset and meet all the clinical, limitations, other authors conducted a regional study in the USA physiological and radiographic criteria for ARDS. Other diseases with and found that the incidence of acute lung injury (including ARDS infectious etiologies could also simulate the syndrome. In 2004, one and less serious levels of hypoxemia, but with the other findings of group of authors published a study with the objective of evaluating the the syndrome) was 78.9 for every 100,000 inhabitants.14 Mortality role of the lung biopsy in ARDS. In that study, involving 57 patients, data are also limited. Most studies are conducted in specific patient the most common alternative or concomitant diagnosis to ARDS were groups with strict inclusion and exclusion criteria, with the objective infection in 8 cases, alveolar hemorrhage in 5 cases and bronchiolitis of assessing treatment strategies rather than mortality. Among these, obliterans organizing pneumonia in 5 cases, as well as drug reactions, two more recent studies reported mortality rates of 35% and 40%. lymphangitic carcinomatosis, chronic eosinophilic pneumonia, The epidemiologic trials conducted by these two groups of authors allergic bronchopulmonary aspergillosis and cardiogenic pulmonary produced similar outcomes, both reporting an ARDS mortality rate edema in 1 case each. Based on the results, the treatment for most of of 41.1%. However, these numbers demonstrate the importance of the patients was changed, with the addition of specifictherapy in 60% recognizing ARDS, and the need for a reliable clinical definition, and the discontinuation of unnecessary treatment in 37%. Another since an accurate diagnosis, obtained from histopathological findings, significant implication of these results is that it is possible that not is not possible in most cases. The principal finding of many studies all of the patients involved in the studies investigating different was that the sensitivity and specificity of the AECC criteria to ARDS treatment strategies, whether using ventilators or medication, diagnose ARDS, which are widely used in everyday practice and to really had the disease. These studies typically use AECC criteria to conduct clinical trials, are not appropriate. Consequently, the positive define ARDS, which, as demonstrated by our results and those of and negative likelihood ratios obtained cannot safely confirm or other authors, have limited accuracy. Therefore, positive or negative rule out, respectively, a diagnosis of ARDS. Further, in a tailored evidence regarding different ARDS treatments could be determined study that also evaluated the efficiency of the AECC criteria based based on unreliable criteria. This limitation could be minimized by on autopsy results, another group of authors found similar values. establishing stricter inclusion criteria beyond the simple clinical Of 127 patients with clinical ARDS criteria, 43 did not present diagnosis of ARDS. Some authors already limit inclusion in studies histopathological findings of diffuse alveolar damage. The principal of ARDS ventilator strategies to patients that continue to present findings for these patients were: pneumonia, alveolar hemorrhage, radiographic alterations and hypoxemia consistent with ARDS after cardiogenic pulmonary edema, pulmonary embolism and pulmonary a minimum positive end-expiratory pressure of, for example, 10cm H O has been applied for at least 24 hours. Even if this type of strategy interstitial disease secondary to chemotherapy. In contrast, the autopsy 2 confirmed the presence of diffuse alveolar damage in the 27 patients does not improve diagnostic accuracy, it establishes a more restrictive that did not present clinical criteria for the ARDS diagnosis. Of those level of lung injury severity, increasing the reproducibility of the 13 27, 12 had been diagnosed with pneumonia, 12 had been diagnosed results obtained. with cardiogenic pulmonary edema, and 3 had not been diagnosed The differences between Pulmonary and with any respiratory disorder. These discrepancies between clinical Extrapulmonary acute respiratory distress syndrome and histopathological findings in relation to ARDS reveal the limited accuracy of the AECC criteria, which were found to have a sensitivity Since its initial description, the acute respiratory distress syndrome of 75%, a specificity of 84%, a positive likelihood ratio of 4.7 and a has been considered as a morphological and functional expression of negative likelihood ratio of 0.3. a similar underlying lung injury caused by a variety of insults. In fact, Ashbaugh et al.2 in defining this syndrome stated that “The etiology of The reason for this low accuracy is that, although ARDS is a this respiratory distress syndrome remains obscure. Despite a variety complex inflammatory condition that attacks the alveolar-capillary of physical and possibly biochemical insults, the response of the lung barrier, involving various mediators and the development of edema was similar in all 12 patients. In view of the similar response of the and alveolar collapse, the AECC diagnostic criteria only reflect the lung to a variety of stimuli, a common mechanism of injury may be consequences of these alterations on the chest x ray and gas exchange, postulated”.2 This observation used the term syndrome to refer to “a

Citation: Zwer F. Acute lung injury & acute respiratory distress syndrome - part I. J Anesth Crit Care Open Access. 2015;3(5):11‒12. DOI: 10.15406/jaccoa.2015.03.00109 Copyright: Acute lung injury & acute respiratory distress syndrome - part I ©2015 Zwer 11 group of symptoms and signs of disordered function related to one alterations in pulmonary ARDS and extrapulmonary ARDS are another by means of some anatomic, physiologic, or biochemical reported in (Table 12). peculiarity”. In 1994, the American-European Consensus Conference A direct insult has been studied in experimental models by using defined two pathogenetic pathways leading to ARDS: a direct intratracheal instillation of endotoxin, complement, tumor necrosis (primary or pulmonary) insult that directly affects lung parenchyma factor (TNF), or bacteria. After a direct insult, the primary structure and an indirect (secondary or extrapulmonary) insult that results from injured is the alveolar epithelium, while the capillary endothelium is an acute systemic inflammatory response. The differentiation between roughly normal. This causes activation of alveolar macrophages and direct and indirect insult is often straightforward as for primary neutrophils and of the inflammatory network, leading to intrapulmonary diffuse pneumonia or ARDS originating from intra-abdominal sepsis. inflammation. An increased amount of apoptotic neutrophils and In other situations, the precise identification of the pathogenetic altered type I and type II cells has been reported as well as an increase pathway is somewhat questionable, as for trauma or cardiac surgery. in interleukins (IL)-6, 8 and 10 in the bronchoalveolar lavage (BAL) The distinction, however, was mainly speculative until Gattinoni et al. in direct injury compared to indirect injury. The prevalence of the reported possible differences in the underlying pathology, respiratory epithelial damage determines a localization of the pathological mechanics, and response to PEEP in pulmonary ARDS (primarily abnormality in the intra-alveolar space, with alveolar filling by pneumonia) and extrapulmonary ARDS (primarily due to abdominal edema, fibrinous exudate, collagen, neutrophilic aggregates, and/ disease). In (Table 11) are reported the some of the underlying or blood, with a minimum interstitial edema. This pattern has often etiologies in pulmonary ARDS and extrapulmonary ARDS. ARDS been described as pulmonary consolidation, probably representing a occurs following a variety of risk factors. Strong evidence that supports combination of alveolar collapse and prevalent fibrinous exudates and a causeand- effect relationship between ARDS and risk factors was alveolar wall edema in pulmonary ARDS. identified for sepsis, trauma, multiple transfusions, aspiration of gastric contents, pulmonary contusion, pneumonia, and smoke inhalation. An indirect insult has been studied in experimental models by However, only a few studies have investigated the prevalence and intravenous or intra peritoneal toxic injection. After an indirect insult, mortality considering pulmonary ARDS and extrapulmonary ARDS. the lung injury originates from the action of inflammatory mediators In the majority of available studies the prevalence of pulmonary released from extra pulmonary foci into the systemic circulation. ARDS was higher compared to extrapulmonary ARDS, varying In this case, the first target of damage is the pulmonary vascular from 47 to 75% of all cases. In the most recent retrospective analysis endothelium, with an increase of vascular permeability and interstitial of patients enrolled in the Acute Respiratory Distress Syndrome edema. A decreased amount of apoptotic cells has been described in Network (ARDSNet) trial of low tidal volume ventilation, roughly experimental model of extra pulmonary ARDS as well as a decreased an equal proportion of pulmonary ARDS and extrapulmonary ARDS amount of ILs in the BAL. Thus, the pathological alteration due were identified. It has been reported that pulmonary trauma was to an indirect insult is primarily micro vascular congestion and associated with higher survival rate, whereas opportunistic pneumonia interstitial edema, with relative sparing of the intra-alveolar spaces. had a lower survival rate. Among complications, acute renal failure, Histologically the ARDS lung is characterized by diffuse lung pulmonary infection, and bacteraemia seem to be independent factors damage with subdivision of temporal course in early and late lesions, associated with increased mortality. However, the reported mortality designated as acute and chronic fibro proliferative diffuse alveolar in patients with ARDS attributable to pulmonary and extrapulmonary damage. The acute stage of diffuse lung damage by interstitial and causes varies considerably. In one study a direct pulmonary insult intra alveolar edema and hyaline membrane. This stage is followed triggering ARDS was identified as being associated with increased by consecutive proliferation by fibroblastic cells characterized by mortality, whereas in another study no relationship was found between chronic and or fibro proliferative damage. The disease process finally direct pulmonary insults and increased mortality (36% and 34% leads to the gross destruction of the pulmonary lobes resulting in mortality for pulmonary and extrapulmonary causes, respectively). fibrosis and honeycombing. A recent some studies have described Moreover, in the same cohort of patients, the proportion of patients the morphological differences between pulmonary lesions in patients in whom organ failure developed the pulmonary and extrapulmonary with pulmonary ARDS and extra pulmonary ARDS. They found a was equal between groups, and the proportion achieving liberation predominance of alveolar collapse, fibrinous exudate and alveolar from mechanical ventilation at 28 days was also identical. The lack of wall edema in pulmonary ARDS. However the acute inflammatory agreement among various studies can be explained by differences in: phase of lung injury is also associated with fibro proliferative response that leads to alveoli obliteration and derangement in the a. Baseline status. spatial distribution of the extracellular matrix. Also it is recently b. The prevalence of the disease precipitating ARDS in each Centre. reported an increased collagen content in pulmonary ARDS than in extra pulmonary ARDS in the early phase of the disease, while no c. The impact of therapy. differences were observed concerning the elastic fibers ontent. It is d. The overall distribution of these factors in the studied population. therefore concluded that extracellular matrix remodeling occurs early in the development of ARDS and appears to depend on the site of Thus, it is not known whether different clinical management the initial insult, being prevalent in pulmonary ARDS. In general and ventilatory treatment modified accordingly with the different these experimental and in vivo findings suggest that the damage in pathophysiological characteristics could improve outcome (Table 11). the early stage of direct insult is primarily focused on the alveolar The alveolar-capillary barrier is formed by two different structures, epithelium, whereas in indirect injury on the vascular endothelium. the alveolar epithelium and the vascular endothelium. Traditionally, it The inflammatory agents are more increased in the serum in extra has been though that insults applied to the lung, through the airways pulmonary ARDS, while in the BAL in pulmonary ARDS. However, or the circulation, result in diffuse alveolar damage. Although many it is worth noting the possible co-existence of the two insults: one lung insults may converge in the stage of ARDS, it is really wonder with direct injury (as pneumonia) and the other with indirect injury if, in early stages, a direct or indirect insult to the lung may have (through mediator release from the original pneumonia).15 different manifestations. The different histological and biochemical

In recent years, a number of studies have identified differences infection and the development of severe respiratory failure (usually by computed tomography (CT) between pulmonary ARDS and extra within 1 week), can favor some initial diffusion of inflammatory pulmonary ARDS. It is found that by performing three representative agents, which can explain the presence of amounts of ground- scans at the apex (top of the upper aortic arch), at the hilum (first glass opacification in pulmonary ARDS from community-acquired section below the carina), and at the base (2 cm above the highest pneumonia. Moreover, the aggressive therapeutic management diaphragm). The entilatory setting was not standardized during ventilator-associated pneumonia, and thus a potential reduction in scans. The lung was scored as follows: “normal lung,” “ground-glass release of inflammatory agents in the peripheral circulation, may limit opacification” (mild increased attenuation with visible vessels), and the radiological pattern to consolidation and/or atelectasis. “consolidation” (markedly increased attenuation with no visible However, with all the limits and somewhat arbitrary classification vessels). It is found that in extra pulmonary ARDS, ground-glass of patients and interpretation of morphological observation, these opacification was more than twice as extensive as consolidation findings support the hypothesis that the radiological pattern is different (Figure 1A & B). This contrasted markedly with pulmonary ARDS, in in pulmonary ARDS and extra pulmonary ARDS. It can be concluded which there was an even balance between ground-glass opacification that: and consolidation. When the type of opacification between the two groups was compared, the patients with extra pulmonary ARDS had i. In ARDS, the increase in the lung densities is most prominent 40% more ground-glass opacification than did those with pulmonary in the dependent lung regions in the supine position but may, ARDS. Conversely, the pulmonary ARDS patients had ˃50% more in a minority of patients, be more homogeneously distributed consolidation than did those with extra pulmonary ARDS. It is also throughout the lung parenchyma. found differences in the regional distribution of the densities. In extra pulmonary ARDS ground-glass opacification was greater in the ii. In pulmonary ARDS due to community-acquired pneumonia, central (hilar) third of the lung than in the sternal or vertebral third. two prevalent patterns have been described: the first, extensive There was no significant craniocaudal predominance for ground-glass consolidation and air bronchograms in the dependent part of the opacification or consolidation, but consolidation showed a preference lung together with ground-glass opacification, or the second, for the vertebral position over the sternal and central positions. homogeneous diffuse interstitial and alveolar infiltration, without In extra pulmonary ARDS ground-glass opacification was evenly evidence of atelectasis. distributed in both the craniocaudal and sterna vertebral directions. iii. In pulmonary ARDS, due to ventilator-associated pneumonia, Consolidation tended to favor the middle and basal levels, but also densities in the dependent part of the lung (likely atelectasis) are favored the vertebral position. The total lung disease was almost prevalent with the remaining nondependent lung substantially evenly distributed between the left and right lungs in both pulmonary normal. ARDS and extra pulmonary ARDS. However, grossly asymmetric disease was always due to asymmetric consolidation. Moreover, iv. On the contrary in extra pulmonary ARDS, there is predominantly the presence of air bronchograms and pneumomediastinum were ground-glass opacification. prevalent in pulmonary ARDS, while emphysema-like lesions (bullae) Traditionally, the mechanical alterations of the respiratory system were comparable in both types of ARDS (Figure 1A & B). observed during ARDS were attributed to the lung because the chest It was reported that a significantly higher incidence of intense wall elastance was considered nearly normal. Studies in which parenchymal opacification in nondependent areas of the lung in respiratory system, lung, and chest wall mechanics were partitioned patients with direct insults (indicative of consolidation secondary to have proved this assumption wrong. The present investigations inflammatory infiltrate), but no other differences emerged between the consistently found that the elastance of the respiratory system was two types of patients. Moreover, the extent of intense parenchymal similar in pulmonary ARDS and extra pulmonary ARDS, but the opacification in nondependent areas of the lung was inversely related elastance of the lung was higher in pulmonary ARDS, indicating a to the time from intubation to CT. It was concluded that differentiating stiffer lung. Conversely, the elastance of the chest wall was more than between pulmonary ARDS and extra pulmonary ARDS on the basis 2 folds higher in extra pulmonary ARDS than in pulmonary ARDS, of CT findings is not straightforward, and that no single radiological indicating a stiffer chest wall. The increase in the elastance of the chest feature is specifically associated with lung injury of either type. It is wall was related to an increase in the intra-abdominal pressure, which currently found that all the patients with ARDS showed consolidation was 3 folds greater in extra pulmonary ARDS. In critically ill patients, opacities in the dependent part of the lung (Figure 2A). However data on intra abdominal pressure are surprisingly scanty. In most of differently from pulmonary ARDS originating from community- the current studies patients, the elevated values could be explained acquired pneumonia, in ventilator-associated pneumonia the amount by primary abdominal disease or edema of the gastrointestinal tract. of aerated lung was increased while ground-glass opacification was The sonographic findings of the abdomen were analyzed in normal less compared to community-acquired pneumonia. However, when spontaneously breathing subjects, in patients with extra pulmonary these patients were turned prone a marked reduction of previously ARDS due to abdominal sepsis, and in patients with pulmonary dependent densities was found (nondependent in prone, (Figure 2B). ARDS due to community-acquired pneumonia. In the normal subjects This suggests that lung areas previously considered consolidated due it was difficult to recognize the abdominal wall and the gut anatomical to ventilator associated pneumonia, were not really consolidated but structure. In the patients with extra pulmonary ARDS and related mainly atelectatic.16 Application of recruitment maneuvers or PEEP abdominal problems, the increased dimension and thickness of the gut, with intraluminal debris and fluid and with reduced peristaltic (up to 15cmH2O) were unsuccessful to reopen these zones in supine position, likely because of a marked in homogeneity of pulmonary movements, were visible. In the patients with pulmonary ARDS, parenchyma (well aerated-elastic in nondependent and non-aerated- the dimension of the gut were slightly increased while the gut wall stiff in dependent zones). Thus, it is possible to hypothesize that thickness was not increased, without any consistent debris or fluid. the pathophysiology and the lung morphology in pulmonary ARDS Thus, it is evident that patients with abdominal problems present may be different in community-acquired pneumonia and ventilator- important anatomical alterations of the gut, which can explain the associated pneumonia. It is possible that the period of time from the increased intra-abdominal pressure. Thus, these findings suggest that

Citation: Zwer F. Acute lung injury & acute respiratory distress syndrome - part I. J Anesth Crit Care Open Access. 2015;3(5):11‒12. DOI: 10.15406/jaccoa.2015.03.00109 Copyright: Acute lung injury & acute respiratory distress syndrome - part I ©2015 Zwer 13 in ARDS the increased elastance of the respiratory system is produced male and female patients, ARDS declines with increasing testosterone by two different mechanisms: in pulmonary ARDS a high elastance levels.18 Despite the increased incidence in ARDS, the mortality of the lung is the major component, whereas in extra pulmonary in patients with ARDS does not differ according to gender. These ARDS increased elastance of the lung and of the chest wall equally findings are not fully explained by sex hormones, but there is evidence contributed to the high elastance of the respiratory system. Moreover, that the relationship between pro-inflammatory estrogens and immune it was found that respiratory resistance, partitioned into its airway and depressing testosterone and development of ARDS are important viscoelastic components, was comparable in pulmonary ARDS and an regardless of gender.19 extra pulmonary ARDS. However, the resistance of the chest wall was also elevated in extra pulmonary ARDS and significantly correlated to intra-abdominal pressure, suggesting that intra-abdominal pressure can affect the viscoelastic properties of the thoraco abdominal region. However, it is important to consider that most of the patients in the extra pulmonary ARDS had ARDS caused by intra-abdominal pathological conditions, and it seems likely that some of the changes seen in chest wall elastance relate to intra-abdominal mechanics and effects on diaphragmatic movements. Altered lung elastance with relatively normal chest wall elastance was also found in patients Figure 1 A computed tomography scan of extra pulmonary acute respiratory affected by severe P. carinii pneumonia, and in patients with ventilator- distress syndrome at end expiration. There is a predominantly ground-glass Opacification. associated pneumonia that usually present the same histopathology as pulmonary ARDS.17 B A computed tomography scan of pulmonary acute respiratory distress syndrome at end-expiration. There is extensive consolidation, with an Gender and acute respiratory distress syndrome approximately equal amount of normal lung and ground-glass opacification and air bronchograms. The Acute Respiratory Distress Syndrome remains a considerable contributor tomorbidity and mortality after critical injury. Several authors have hypothesized gender as accounting for differences in outcomes following trauma, particularly in animal models. It was hypothesized that the pro-inflammatory properties of estrogens would predispose females to developing ARDS (Figure 3). Gender differences in the prevalence of asthma are well described with females being at a higher risk. For instance in a recent analysis of patients hospitalized for an asthma exacerbation in England, women had a higher death rate. Female gender has also been identified as a risk Figure 2 A computed tomography scan of pulmonary acute respiratory factor for hospitalization in COPD patients. Recent data adds support distress syndrome due to ventilator associated pneumonia at end-expiration. to the hypothesis that the female lung is more prone to injury and the deleterious effects of inflammation. The effect of female gender on the A. Supine position with extensive bilateral apparent consolidations; development of ARDS was independent of the older age and differing B. Prone position, with an almost total clearing of the apparent injury patterns in these patients. It is found that despite higher rates consolidations. This indicates the atelectatic nature of the densities. of ARDS, females with ARDS did not die more frequently than their male counterparts with ARDS. The fact that females are more prone to ARDS following trauma supports the hypothesis that sex hormones may contribute to the propensity to develop lung injury. Estrogens have diverse and extensive immunologic properties, giving plausibility to the fact that the pro-estrous state would be associated with exaggerated inflammation and ARDS. Numerous data Figure 3 The relationship between sex hormones and ARDS stratified by confirms that higher levels of endogenous estrogens are associated gender. with higher rates of ARDS in both genders. However, these differences do not fully explain the difference in ARDS rates by sex since females A. Demonstrates that for both genders, rates of ARDS increase with increasing estradiol. The higher rates of ARDS observed in women are have a higher incidence of ARDS at all estradiol levels than males not fully explained by estrogens, however, since for all estradiol levels, the (Figure 3). rate of ARDS is higher in females. There is similar biologic plausibility for the association between B. Demonstrates that for both genders, rates of ARDS decrease with lower testosterone and higher rates of ARDS since testosterone is increasing testosterone. generally considered immune depressing. Also, global hypothalamic- C. Demonstrates the relationship between testosterone and estradiol pituitary-gonadal axis suppression, and therefore, testosterone (testosterone to estradiol ratio) and rates of ARDS. For both genders depression is related to illness severity. Many data confirms this a higher ratio appears protective, with the lowest rates of ARDS being relationship in both genders. Anyhow, it was concluded that females expected in patients with ratios greater than 50. are more likely than males to develop ARDS following critical injury. However, regarding the concept of sex hormones, specifically Recurrent acute lung injury estrogens, having immunologic properties enabling the development of lung injury. For both male and female patients, ARDS increases With the improvement of ALI survival in population it was in incidence with increasing estradiol levels. Additionally, for both observed that a significant number of patients who had more than one episode of ALI (recurrent ALI). Gastroesophageal reflex disease

Table 13 Association with recurrent ALI and single ALI5

Exposure frequency Discordant pairs* Concordant pairs* Variables Recurrent ALI% Single ALI% +/ ̶ ̶/+ +/+ ̶/ ̶ Gastro-esophageal reflex disease 79 42 7 0 8 4 Proton pump inhibitors use 42 42 6 6 2 5 H2 blocker use 32 5 5 0 1 13 Aspiration of gastric contents 37 5 7 1 0 11 Chronic pain 5 5 1 1 0 17 Chronic opioid use 21 5 4 1 0 14 Smoking 68 47 7 3 6 3 Chronic alcohol use 10 5 1 0 1 17 Obstructive lung disease 31.6 21.1 6 4 0 9 Immunocompromised 10.5 15.7 1 2 1 15 Diabetes mellitus 31.6 15.7 5 2 1 11 Body mass index (BMI) ≥ 30 31.6 21 4 2 2 11 Transfusion 26 5 5 1 0 13 +/−= matched pair with Recurrent exposed, Single unexposed; −/+ = Recurrent unexposed, Single exposed; +/+ = both Recurrent and Single exposed; −/− = both Recurrent and Single unexposed. Table 14 Association with recurrent ALI and No ALI5

Exposure frequency Discordant pairs* Concordant pairs* Variables Recurrent ALI% Single ALI% +/ ̶ ̶/+ +/+ ̶/ ̶ Gastro-esophageal reflex disease 79 42 7 0 8 4 Proton pump inhibitors use 42 42 6 6 2 5 H2 blocker use 32 5 5 0 1 13 Aspiration of gastric contents 37 5 7 1 0 11 Chronic pain 5 5 1 1 0 17 Chronic opioid use 21 5 4 1 0 14 Smoking 68 47 7 3 6 3 Chronic alcohol use 10 5 1 0 1 17 Obstructive lung disease 31.6 21.1 6 4 0 9 Immunocompromised 10.5 15.7 1 2 1 15 Diabetes mellitus 31.6 15.7 5 2 1 11 Body mass index (BMI) ≥ 30 31.6 21 4 2 2 11 Transfusion 26 5 5 1 0 13 +/− = matched pair with Recurrent exposed, No ALI unexposed; −/+ = Recurrent unexposed, No ALI exposed; +/+ = both Recurrent and No ALI exposed; −/− = both Recurrent and No ALI unexposed.

Table 15 Signs and Symptoms That Suggest Specific Causes of Acute Respiratory Distress Syndrome24

Signs/Symptoms Possible cause Most common Productive cough, fever, pleuritic chest pain. Pneumonia Infection plus some of the following findings: temperature > 38.3˚C or < 36˚C; pulse > 90 beats/minute; tachypnea; altered mental status; white blood cell count > 12,000/mm3 (12 × 109 per L), < 4,000 mm3 Sepsis (4 × 109 per L), or > 10% immature forms; elevated C-reactive protein level; arterial hypotension; acute oliguria; hyperlactatemia. Less common History of institutionalization or mental retardation, decreased Glasgow Coma Scale score. Aspiration History of drug abuse, especially inhalational. Drug toxicity Facial burns, singed eyebrows, carbonaceous sputum, and history of working near organic solvents or Inhalation injury toxic chemicals. History of needing water rescue, hypothermia. Near drowning Fever, rhinorrhea, cough, history of prematurity or congenital heart disease. Respiratory syncytial virus Symptoms of acute lung injury and blood transfusion within the previous six hours. Transfusion-related ALI Bruising over the chest wall, associated injuries, history of motor vehicle crash or fall from a height. Trauma Table 16 Differential Diagnosis of Acute Hypoxia24

Condition Clues to Diagnosis More common Asthma Cough, wheeze, response to bronchodilator. Chronic obstructive pulmonary disease Decreased air movement, prolonged expiratory phase. Congestive heart failure Jugular venous distension, peripheral edema, third heart sound. Pneumonia* Productive cough, fever, pleuritic chest pain. Less common Acute eosinophilic pneumonia Fever, cough, diffuse infiltrates, increased eosinophils on bronchoalveolar lavage. Acute onset; exposure to inciting organic antigen, such as those found in bird feathers, molds, Hypersensitivity pneumonitis and dust. Pneumothorax Acute onset of dyspnea, pleuritic chest pain; tall and thin body habitus. Salicylate toxicity History of suicide attempt, hyperventilation, tachycardia, seizure. Sepsis* Fever, tachypnea, tachycardia, elevated or depressed white blood cell count. *Pneumonia and sepsis are leading causes of acute respiratory distress syndrome, but may be present in patients who do not meet diagnostic criteria for the syndrome. Table 17 Factors That Distinguish ARDS, Congestive heart failure and Pneumonia. [+= present, –= not present, +/– = may or may not be present]24

Distinguishing factor ARDS Congestive Heart failure pneumonia Symptoms Dyspnea + + + Hypoxia + + + Tachypnea + + + Pleuritic chest pain +/ ̶ ̶ + Sputum production +/ ̶ ̶ + Signs Rales + + + Fever +/ ̶ ̶ + Edema ̶ + ̶ Jugular venous distension ̶ + ̶ Third heart sound ̶ + ̶ Studies Hypoxemia + + + Bilateral infiltrates + +/ ̶ +/ ̶ Pulmonary wedge pressure ≤ 18 mmHg + ̶ ̶

PaO2/FiO2 ≤ 200 + ̶ ̶ Localized infiltrate ̶ ̶ + Elevated brain natriuretic peptide level ̶ + ̶ Cardiac enlargement ̶ + ̶ Responses Antibiotics ̶ ̶ + Diuretics ̶ + ̶ Oxygen ̶ + +

Recent studies indicate that the incidence of ALI/ARDS is 22- Nonetheless, the death rates were not statistically different 86 cases per 100,000 person-years and up to 64 cases per 100,000 between patients with ALI who were admitted to the ICU and those person-years, respectively.14 A large, prospective European trial who were not (22% versus 27%). Although the confidence intervals estimated that 7.1% of patients admitted to an ICU and 16.1% of all around these estimates are wide, they certainly do not suggest that patients on mechanical ventilation develop ALI or ARDS. The in- these patients with ALI were kept on the floor because they were hospital mortality rate for these conditions is estimated to be between all going to do well. It is unknown whether admission to the ICU to 34 and 55%. Risk factors for mortality include increasing age, receive therapies such as more vigorous resuscitation or non-invasive worsening multiorgan dysfunction, and presenc of pulmonary and ventilation would change this outcome (Figure 4). It was found that non pulmonary comorbidities, higher Acute Physiology and Chronic on average, patients progressed quickly from development of clinical Health Evaluation (APACHE) II score, and acidosis. Most ARDS- insult, to ICU admission, to diagnosis of ALI/ARDS. The finding related deaths are due to multiorgan failure. Refractory hypoxemia that most cases of ARDS occur quickly after the onset of the clinical accounts for only 16% of ARDS-related deaths. In children, ARDS predisposition is not new; however, the knowledge was extended in is less common and less likely to lead to death. In a 2009 study of two ways: patients six months to 15 years of age, the reported incidences of ALI/ 1. It was found that most patients entering the ICU do so on the day ARDS were 9.5 and 12.8 per 100,000 person-years, respectively, with of developing their clinical insult is new, and it underscores the a combined in-hospital mortality rate of 18%. potential need for rapid intervention in these patients. However, because the presenting symptoms of ARDS are 2. It was observed a significantly longer time to ALI/ARDS nonspecific, physicians must consider other respiratory, cardiac, development for extrapulmonary risk conditions compared with infectious, and toxic etiologies (Table 16). Patient history (e.g., pulmonary risk conditions (Figure 5). comorbidities, exposures, medications) in conjunction with a physical examination focusing on the respiratory and cardiovascular 3. It is worth noting that relatively few patients initially diagnosed systems can help narrow the differential diagnosis and determine the with ALI went on to develop ARDS (13%); this is a significantly optimal course of treatment. Mostly ARDS must be differentiated lower proportion than the 55% conversion rate reported in a from congestive heart failure and pneumonia (Table 17). Congestive recent multicentre observational study22 (Figure 4). heart failure is characterized by fluid overload, whereas patients diagnosed with ARDS, by definition, do not show signs of left atrial hypertension or overt volume overload. Patients with congestive heart failure may have edema, jugular venous distension, third heart sound, an elevated brain natriuretic peptide level, and a salutary response to diuretics. Patients with ARDS would not be expected to have these findings. In other aspect, because pneumonia is a leading cause of ARDS, distinguishing patients with uncomplicated pneumonia from those who have pneumonia complicated by ARDS presents a greater diagnostic challenge. In general, a patient with uncomplicated pneumonia may have signs of systemic and pulmonary inflammation (i.e., fever, chills, fatigue, sputum production, pleuritic chest pain, and localized or multifocal infiltrates); accompanying hypoxia should respond to oxygen administration. If hypoxia does not correct with oxygen administration, ARDS should be suspected and confirmed based on AECC diagnostic criteria. In those with combined pneumonia and ARDS, treatment entails antibiotics and ventilator management21 (Table 16). It had been found that a significant number of patients with ALI did not receive care in an ICU; when patients outside the ICU were included, the chance of developing ALI/ARDS with a given clinical insult was substantially lower than reported previously; and the time course from clinical insult to admission to the ICU and diagnosis of ALI/ARDS is rapid, but this process may take longer for extra pulmonary ALI/ARDS. It had been also found that more than half the patients with ALI (PaO2/FiO2 200 to 300mmHg) were managed Figure 4 Prevalence of ALI and ARDS by clinical risk condition. entirely outside the ICU. This has important implications for the A. The proportion of patients with each clinical risk condition who went accurate estimation of the true burden of disease in the population, on to develop acute lung injury (ALI; blue columns) or acute respiratory but it also has meaning for clinicians: distress syndrome (ARDS; red columns) is shown for all patients. B. And for only those admitted to the intensive care unit. a. For clinicians managing patients on medical and surgical wards, In both panels the number of patients at risk with each clinical insult is it is important to realize that many patients with acute lung injury displayed numerically below each category label. will be managed entirely outside the ICU. These patients with ALI will need different therapy from patients with cardiogenic In general it was observed that the time course from clinical insult pulmonary edema, for whom they may be mistaken. to diagnosis of lung injury was rapid, but it was longer for extra pulmonary cases. The risk of ARDS was significantly lower than b. For the intensivist, the question is whether these patients with reported previously when patients outside the ICU were considered, ALI should be left on the ward, or whether their outcomes would but rates in ICU patients appeared similar. A significant number of be better if they received care in the ICU (Table 17).

FiO2 difference between the two types of insult patients, given the fact that the community-acquired ARDS had worse oxygenation and more pneumonia. However, other facts related to possible delayed recognition and treatment of ARDS in the community-acquired group offer an alternative explanation. Although the hospital-acquired ARDS group had lower unadjusted hospital mortality, the difference was not statistically significant after adjusting for baseline differences, which may be due to the small sample size; however, prior studies did not find a mortality difference when comparing pulmonary (more common in the community-acquired ARDS patients) versus extra pulmonary ARDS etiologies.25 Figure 5 Time from clinical risk to diagnosis of ALI/ARDS. A. Kaplan–Meier curves displaying time from clinical risk condition to diagnosis of ALI/ARDS are shown for all patients. B. And separated according to pulmonary (red line) versus extra pulmonary (blue line) risk conditions. Timing of the onset of acute lung injury and acute respiratory distress syndrome It was revealed that a new and interesting facts in intensive care Figure 6 Distribution of patients with acute respiratory distress syndrome in medicine regarding the timing of ARDS and its relation to healthcare- relation to recent healthcare contact. system exposure. It is suggested that ARDS is mainly a healthcare- related syndrome, as only 14% of population did not have known healthcare contact prior to ALI/ARDS onset. It is also shown that there is a substantial time gap between hospital admission and ALI/ ARDS onset, which suggests a potential window for future ARDS mechanistic studies and clinical trials of preventive strategies (Figure 6). The principal barrier toward better understanding of the clinical pathogenesis of ALI/ARDS and the design and conduct of ALI/ ARDS preventive strategies is the fact that previous clinical studies focused almost exclusively on patients admitted to the ICU. It is suggested that a substantial time gap is present between the initial development of ARDS risk factors during hospitalization, or even the initiation of mechanical ventilation in critically ill patients admitted Figure 7 Time to acute respiratory distress syndrome during the first week after hospital admission. to the ICU, and the development of ARDS (Figure 7). It is believed that understanding the time course of ALI/ARDS is the first step toward prevention. Subsequent steps can include developing accurate prediction models to identify patients at high risk of ALI/ARDS, and applying preventive or therapeutic strategies, analogous to other several important critical care syndromes, such as stress ulcer bleed, ventilator-associated pneumonia, central venous catheter infection, and venous thrombo embolism. However, observing the evolution of ARDS in rat lung exposed to injurious ventilation prompted the clinical investigation of the relationship between initial ventilator settings and the development of ARDS in patients who did not have ARDS at the outset. Intriguing preliminary results suggested that the processes of care, namely, high-tidal volume mechanical ventilation and liberal transfusion, were more important ARDS risk factors than the initial severity of illness.24 Both ventilator settings and transfusion factors were associated with the development of ARDS, in a dose- dependent manner. Indeed, a quality-improvement intervention aimed at decreasing ventilator tidal volume and liberal transfusion decreased harmful exposures and was associated with a reduced incidence of ARDS in mechanically ventilated patients without ALI at the outset (Figure 7). Figure 8 Frequency of ALI/ARDS development according to predisposing It was found that patients with community-acquired ARDS were conditions. The figure depicts the frequency of ALI/ARDS development in more likely to be medical patients (85%) with pneumonia (59%), subsets of patients with different risk factors. Because the risk factors are not whereas those who developed ARDS after hospital admission were mutually exclusive, the patients who presented with more than one risk factor may be counted more than once. more likely to be surgery patients (54%). It was suggested that

Lung Injury Prediction Score ventilation, and aspiration. In fact, single-center studies have shown a significant decrease in the incidence of ALI in association with Lung injury prediction score [LIPS]: Investigations of therapeutic changes in health care delivery. Given the high mortality associated interventions in acute lung injury and its more severe form, acute with the development of ALI and the significant functional and respiratory distress syndrome, have concentrated on patients with cognitive impairment experienced by survivors of ALI, prevention of established disease. Proven and effective treatments at that point are ALI may improve survival and long-term functional outcomes better limited. Indeed many treatments targeting the mechanisms identified than interventions aimed at reducing mortality after development in promising preclinical studies have failed to improve patient of ALI. Although ALI development markedly increased the risk of outcomes. Failed trials likely result, in part, from delayed recognition death, the observed mortality rate of 23% is lower than previously of patients at risk and the subsequent development of the full-blown reported. The exclusion of patients with established ALI transferred syndrome. Preventing the development of ALI may be more effective from outside facilities, the inclusion of patients who did not require in improving outcomes. Unfortunately, delivering preventative ALI invasive mechanical ventilation, and secular trends in ALI prognosis therapies to at-risk individuals has received little attention, in time any provide potential explanations for the observed findings.26 intervention decreasing the incidence of ALI will significantly impact the mortality, morbidity, and intensive care unit use associated with this syndrome. A major obstacle to any early intervention or preventive studies is our inability to anticipate which patients are likely to develop ALI. Epidemiologic data suggest that ALI is rarely present at the time of initial emergency department evaluation or hospital admission for high-risk elective surgery, but develops over a period of hours to days in a subset of at risk patients. A recent Spanish study reported that the vast majority of patients with predisposing conditions never develop ALI, making the enrollment of unselected patients into ALI prevention studies neither feasible nor efficient. Moreover, a large number of patients who ultimately would not develop ALI would be subjected to the risk and expense of a prevention strategy. Recent studies have identified several risk modifiers that may alter the likelihood of ALI development in patients with predisposing conditions. These include alcohol abuse, hypoalbuminemia, tachypnea, oxygen supplementation, Figure 9 Calibration curves for APAHCE II, SAPS II, GOCA, and LIS. Unmarked chemotherapy, obesity and diabetes mellitus, although whether line (black line) represents the line of perfect correspondence between these factors are independent of one another is unclear. The lack actual and predicted risk of death; marked lines (colored lines) represent the of a validated risk model that confirms and consolidates these risk calibration curves. The models used for calibration curves were made using modifiers prevents the systematic determination of a population at patient location before MICU admission in addition to severity scores (Jegal high risk for developing ALI and is a major limitation to studies aimed 2008 with modification). at prevention or early intervention in ALI. However, recently observations reported an ALI prediction model, the Lung Injury Prediction Score (LIPS), incorporating the risk factors and risk modifiers present at the time of hospital admission, before ALI onset. It is found that the frequency of ALI varied according to predisposing condition (Figure 8), with the highest rate of ALI occurring after smoke inhalation (26%) and the lowest rate occurring in pancreatitis (3%) (Figure 8). The LIPS model has several strengths and it is both unique and easy to perform: a. It includes clinical information strongly associated with ALI in multiple studies and readily available at the time of the admission. It uses information that is clearly defined and routinely available in the medical record and as part of usual care. b. The model identifies at-risk patients early in the course of illness and before ICU admission. c. The model also includes a previously understudied group of patients at high risk for ALI who undergoes high-risk elective (cardiothoracic) surgery. Figure 10 Increased permeability pulmonary edema is a hallmark of ALI/ In clinical practice the LIPS model may potentially be used to ARDS. Edema fluid to plasma protein concentrations expressed as a ratio alert the providers to patients at risk for ALI. Although no specific to determine whether the edema fluid is a transudate as in hydrostatic intervention has been shown to prevent ALI in patients at risk, pulmonary edema (˂0.65) or an exudate (˃0.65) as in increased permeability pulmonary edema (ALI/ARDS). The pulmonary edema fluid samples were applying a model such as LIPS to identify high-risk patients may alert obtained from patients within the 15 minutes of entdotracheal intubation for physicians to avoid specific second-hit hospital exposures, such as acute respiratory failure. blood product transfusions, amiodarone, high tidal volume mechanical

The efficacy of GOCA scoring system in patients with ARDS: To critically ill patients, not specifically for patients with ARDS. It was compare mortality rates between different institutions, the effects of found that LIS was inferior to APACHE II and SAPS II in predicting newer treatment methods, and to identify high mortality groups, a ARDS mortality. LIS is obtained by dividing the aggregate sum by scoring system that can objectively measure the severity-of-illness the number of components that are used. There are four components; of ARDS patients would be helpful. Over the past 20 years, there the extent of alveolar consolidation (chest radiography) (0-4), the have been numerous efforts to develop models that provide severity- degree of hypoxia (0-4), the degree of respiratory system compliance of-illness measures to objectively describe ICU populations and (0-4), and the degree of PEEP (0-4) (Table 5). The PaO2/FiO2 ratio ICU risk prediction models were constructed for heterogeneous was not different between survivors and non-survivors, and this lack patients in ICUs. Severity scoring systems that can be applied to of relationship between the degree of hypoxia and mortality might patients with ARDS can be divided into two types. One type aims have contributed to the shortage of discriminative power of LIS. The to estimate general health condition of critically ill patients, and relationship between hypoxia and mortality of ARDS patients remains the other focuses on the severity of lung injury. Among the severity controversial, as has been reported in previous studies. scoring systems that have been proposed for critically ill patients, Previous studies have also reported that LIS was not suitable for the acute physiology and chronic health evaluation (APACHE) and predicting ARDS patient outcome and the discriminative power of the simplified acute physiology score (SAPS) systems are frequently LIS for overall survival was inferior to SAPS or APACHE II scores. used. The performances of these systems in ICUs have been reported There are two possible explanations for the inferiority of the LIS: as satisfactory. APACHE II and SAPS II were originally developed for predicting the prognosis of critically ill patients. Both of these 1. The development of many strategies that support respiratory scoring systems focus on evaluating the general health of the patients. ability have led to general health condition, rather than lung By contrast, the lung injury score (LIS) and the Gas exchange, Organ function, being the major prognostic factor even in patients with failure, Cause, Associated disease (GOCA) score were developed ARDS. specifically for patients with ARDS to define or stratify the disease (but not to predict prognosis). LIS mainly focuses on the severity of 2. LIS was originally developed to define ARDS, not to predict 5 lung injury. The scoring systems for general critically ill patients may prognosis. not accurately predict the prognosis in highly specialized patients The GOCA stratification system was proposed by the American such as ARDS. Furthermore, the scoring systems that focus on European Consensus Conference on ARDS to assess the severity of mainly lung condition also can not predict the prognosis of ARDS acute lung injury and the associated clinical features. GOCA considers because the degree of hypoxia was not correlated with the mortality not only the severity of lung injury but also a few general conditions of those patients. Theoretically, GOCA can be superior to APACHE such as the number of organ failure and associated diseases. The II or SAPS II for predicting the prognosis of patients with ARDS GOCA score is the sum of four variables: because it considers the severity of lung injury as well as general health condition. The mortality predictive performance of the GOCA A. The severity of gas exchange (0-3). system for ARDS patients has not been adequately addressed, and B. The number of organ failure (0-3). there are few reports that have evaluated the overall performances of LIS, APACHE II, and SAPS II on ARDS patients. However, two C. The cause of lung injury (0: lung only, 1: direct lung injury, and hypotheses were formed: 2: indirect lung injury) a. One is that neither the severity scoring systems that reflect D. The associated diseases (0: no associated disease that will cause general condition nor those reflect severity of lung injury can death within 5 years, (coexisting diseases that will cause death accurately predict prognosis of patients with ARDS when used within 5 years but not within 6 months, and 2: coexisting diseases alone. Therefore, GOCA, which reflects general health condition that will cause death within 6 months). in addition to the severity of lung injury, can be a better mortality Although the GOCA score is not designed to predict outcome, it predictor than APACHE II, SAPS II and LIS. have hypothesized that GOCA can be better than the other scoring b. The other is that the performance of APACHE II and SAPS II systems in predicting prognosis of ARDS patients because it will be improved when they are reinforced by a scoring system considers the general health condition of patients in addition to the that focuses on the severity of lung injury (e.g., LIS) (Figure 9). severity of lung injury. The results generally did not, however, show any predictive advantage of the GOCA system. This may be because The general severity scoring systems, such as APACHE II and the scoring for associated diseases in GOCA is dependent on the SAPS II, showed better performance in predicting mortality of subjective judgment of the attending physician and the differentiation patients with ARDS than LIS, which focuses only on the severity of primary disease is too crude. On the other hand, GOCA may prove of respiratory failure. APACHE II and SAPS II scores have been to be more convenient to use than APACHE II or SAPS II because previously reported to be independent predictors of hospital mortality it requires fewer variables but provides the same predictive power.27 in patients with ARDS. However, these studies evaluated the significance of severity scores using only Student t-tests or logistic ALI/ARDS prediction score: Acute lung injury and its more severe regression. Although these tests have shown excellent performances form acute respiratory distress syndrome are examples of critical on overall critically ill patients, there are only a few reports that have care syndromes with limited treatment options once the condition validated the overall performance of these severity scoring systems in is fully established. Pre-clinical studies support a two-hit model of ARDS patients. The discriminative powers of APACHE II and SAPS ALI/ARDS development whereby exposure to pertinent risk factors II were considered excellent in previous reports addressing overall modify the development and expression of ALI/ARDS in an already critically ill patients. The discriminative powers of these scores susceptible host with predisposing conditions. The condition usually were inferior in this study compared to previous studies, possibly develops in patients with underlying risk factors (pneumonia, severe because these scoring systems were originally developed for overall sepsis, trauma and aspiration) but is modified by different patient’s

Citation: Zwer F. Acute lung injury & acute respiratory distress syndrome - part I. J Anesth Crit Care Open Access. 2015;3(5):11‒12. DOI: 10.15406/jaccoa.2015.03.00109 Copyright: Acute lung injury & acute respiratory distress syndrome - part I ©2015 Zwer 20 characteristics including genetic predisposition, as well as certain edema is the primary physiologic abnormality in the early stages medical interventions (adverse ventilator settings and transfusion of ALI/ARDS. Large animal models with measurements of of alloimunised plasma). Animal models provide compelling hemodynamics and lung lymph flow demonstrated that clinically evidence in support of oxidative stress, lung deformation, loss of relevant causes of ARDS, including live bacteria, endotoxin, and compartmentalization of inflammation and intravascular coagulation microemboli, induced an increase in lung vascular permeability that as the pathogenic mechanisms involved in the development of ALI/ causes protein-rich lung edema. An important clinical study reported ARDS. However, many treatments targeting these mechanisms protein concentrations in the undiluted edema fluid of mechanically have failed to improve patient outcomes despite compelling pre- ventilated patients with acute respiratory failure from severe clinical data. It is probable that inadequate or delayed recognition pulmonary edema. In all subjects with features consistent with ARDS, and treatment of patients at risk of the full-blown syndrome have the ratio of the protein concentration in the edema fluid compared with obscured the therapeutic window. The recent National Institute of than the simultaneously measured plasma sample was ˃0.75, whereas Health workshop prioritized the development of strategies to perform patients with cardiogenic or high pressure, pulmonary edema had an ALI/ARDS prevention trials. The epidemiological data suggest that edema fluid to plasma protein ratio ˂ 0.75. More recent observations ALI/ARDS is rarely present at the time of hospital admission. Rather, are consistent with this finding, showing a separation between patients ALI/ARDS appears to develop over a period of hours to days in this with hydrostatic versus an increased permeability pulmonary edema subset of patients at risk. Unfortunately, clinical studies are usually (Figure 10). Thus, increased permeability edema, interpreted as performed in the ICU setting, enrolling patients with established ALI/ accumulation of protein- rich edema fluid into the alveoli, has become ARDS who are beyond the therapeutic window of potential prevention a hallmark of ALI/ARDS (Figure 11). strategies. This delayed enrolment prevents adequate study of patients Anyhow, subsequently many studies have been done to define at risk. mechanisms that account for the acute increase in lung vascular A significant challenge with early enrolment of patients at risk of permeability. Earlier experiments concentrated mostly on large animal ALI/ARDS into prevention trials is the fact that the majorities of patients models in which pulmonary and systemic hemodynamics could be with predisposing conditions never develops ALI/ARDS and are never measured, whereas more recent studies have used mouse models, admitted to the ICU. This makes the enrolment of unselected patients largely to exploit the opportunity to use specific gene deletions to into ALI/ARDS prevention studies neither feasible nor efficient. The define molecular events that may be pivotal in the development of likelihood of ALI development depends not only on specific risk altered lung vascular permeability. At now mostly the in vitro models factors (from 5% with elective cardiopulmonary bypass to 40% in have used cultured endothelial cells. In parallel with early attempts patients with septic shock), but also on the presence of specific risk to understand the mechanisms that lead to lung edema factors that modifiers. These include alcohol abuse, smoking, hypoalbuminemia, compound the physiologic derangements were considered. One tachypnea, oxygen supplementation, chemotherapy and diabetes hypothesis was that ALI is associated with surfactant dysfunction, mellitus. When comparing the validation cohort (hospitalized patients either because of reduced production or neutralization of surfactant regardless of ICU disposition at the time of admission) to the derivation by the plasma proteins and fibrin that extravasate into the alveoli. cohort (only ICU patients), the proportion of patients with risk factors A decrease in functional surfactant would contribute to alveolar who developed ALI was markedly reduced. Similar results were instability and arterial hypoxemia, potentially increase lung edema recently published by Ferguson et al where only 7% of hospitalized formation and perhaps impair innate immune defenses. Analysis of patients with sepsis, 2% with pancreatitis, 10% of patients with bronchoalveolar lavage samples indicates that the lipid and protein pneumonia and 15% of patients with witnessed aspiration developed components of surface active material are altered in patients with ALI. Indeed, the majorities of patients with predisposing conditions ALI/ARDS. Nevertheless, replacement of surfactant has not reduced never develops ALI/ARDS and are never admitted to the ICU.28 mortality in large clinical trials in adults with ALI, perhaps because, This makes the enrolment of unselected patients into ALI/ARDS unlike infant respiratory distress syndrome, the fundamental lesion prevention studies neither feasible nor efficient without a method in the acute respiratory distress syndrome is not lack of surfactant for identifying those who are at high risk. The failure to take into production by immature alveolar type II cells. In sharp contrast, account multiple triggers that influence ALI/ARDS development has surfactant replacement has substantially reduced mortality in infant probably led to the discarding of a number of potentially important respiratory distress syndrome in preterm infants. The role of lung therapeutic advances in ARDS which may prove to be effective in epithelial cell injury and dysfunction and the mechanisms that specific and highly characterized groups of patients, particularly if regulate removal of alveolar edema fluid, which were not recognized applied early in the course of illness. While some previous studies in early considerations of ALI/ARDS, emerged in experimental and reported the increased risk of ALI/ARDS in the elderly, other studies clinical studies in the 1980s and 1990s. The concept of lung fluid have not confirmed this association. It could be argued that elderly balance incorporates both formation and removal and provides a more patients seem to have an increased incidence of ALI/ARDS as they dynamic concept of the factors that contribute to the net quantity of tend to have more sepsis, pneumonia and aspiration, and require more edema in the lung in animals or humans with ALI (Figure 11). Edema medical interventions. However, in patients admitted to the hospital formation and accumulation in the interstitium and airspaces of the with a risk factor (pneumonia or sepsis), age does not seem to increase lung may be substantial because of a marked increase in lung vascular the risk of ALI/ARDS development. Indeed, recent work implies that permeability, but if alveolar epithelial fluid reabsorption balances the incidence of ALI/ARDS due to community-acquired pneumonia is formation of alveolar edema, then a steady state can be established that lower in patients aged ≥85 years.29 may allow time for recovery from the fundamental cause of lung injury. Perhaps this is why patients who maintain higher rates of alveolar ALI/ARDS: Mechanism Overview epithelial fluid transport in the face of ALI have a better survival. In Pulmonary edema and the early events in ALI/ARDS: Congestion, addition, although a primary event in ALI/ARDS is an increase in lung atelectasis, and pulmonary edema were features of the original vascular permeability, it was apparent from experimental models and description of the syndrome. Within a decade, clinical and experimental clinical observations that the magnitude of lung edema in ALI may studies established the concept that increased permeability pulmonary be substantially increased when lung vascular pressures and volume

Citation: Zwer F. Acute lung injury & acute respiratory distress syndrome - part I. J Anesth Crit Care Open Access. 2015;3(5):11‒12. DOI: 10.15406/jaccoa.2015.03.00109 Copyright: Acute lung injury & acute respiratory distress syndrome - part I ©2015 Zwer 21 are elevated, consistent with the effects of hydrostatic pressure on transvascular flux of fluid and protein. More recently, a large clinical trials are now testing the hypothesis that measures to lower lung vascular pressures in patients with ALI/ARDS can improve clinical outcomes by reducing the quantity of extravasated protein-rich edema fluid in the lung, thus reducing the severity of respiratory failure and ultimately decreasing mortality. In addition to these investigations, the intimate relationship between alveolar edema formation and inflammatory and thrombotic effector mechanisms gradually emerged in the decades after the clinical and physiologic presentations of ALI/ ARDS were described. These concepts were integral to the clinical Figure 11 Early events in ALI/ARDS. A variety of direct (lung infection, studies that demonstrated the variety of triggering disorders that can aspiration) and indirect (sepsis, multiple trauma with shock and large volume be associated with the development of ALI, resulting in injury to the blood replacement) clinical insults lead to ALI. Initial clinical descriptions alveolar barrier (Figure 11). identified pulmonary edema as a major consequence. Subsequent investigations yielded evidence for inflammatory injury to the alveolar–capillary membrane Inflammatory mechanisms in ALI/ARDS: As commonly revealed as a central pathogenetic mechanism. The key effector cells, molecules, and that the altered alveolar barrier function and pulmonary edema are mechanisms that lead to dysregulation of inflammatory and haemostatic central characteristics of ALI/ARDS, mechanisms that could account pathways in ALI/ARDS remain incompletely defined. for the increase in permeability of the alveolar–capillary membrane were poorly understood. Even in early years, however, some investigators believed that inflammation might be involved. One stimulus for this view was the presence of leukocytes together with alveolar edema, hemorrhage, and hyaline membranes in some autopsy specimens (Figure 12). Although subsequent pathologic studies were hampered by heterogeneity in predisposing conditions underlying ALI/ARDS (Figure 11), the risk of lung biopsy in respiratory failure, and the timing and relative infrequency of autopsies, they still provided key information. One study reported purulent exudates in the alveoli of some patients, although the contributions of infection versus inflammatory injury were not dissected. The ultrastructural studies of the lung in patients dying with ALI secondary to sepsis were demonstrated an increased numbers of intravascular and extravascular neutrophils (PMNs), platelets, and fibrin, and both endothelial and epithelial injury, findings that are still incorporated Figure 12 Histologic and ultrastructural analysis of the injured lung has been integral to current concepts of pathogenesis of ALI/ARDS. into recent concepts of inflammatory edema in ARDS (Figure 12). Additional pivotal observations included the presence of PMNs and A. A low-power light micrograph of a lung biopsy specimen collected 2 other leukocytes in bronchoalveolar lavage samples from subjects days after the onset of ALI/ARDS secondary to gram-negative sepsis demonstrates key features of diffuse alveolar damage, including hyaline with ALI/ARDS, studies of PMN-dependent lung injury and edema in membranes, inflammation, intra alveolar red cells and neutrophils, and animal models, and evidence in cell biologic and in vivo analyses that thickening of the alveolar–capillary membrane. PMN oxidants and proteases can injure cells of the alveolar–capillary B. A higher-power view of a different field illustrates a dense hyaline membrane. Subsequent observations are consistent with the concept membrane and diffuse alveolar inflammation. Polymorphonuclear that inflammation is a component of many, and perhaps all, causes leukocytes are imbedded in the proteinaceous hyaline membrane of direct injury to the alveolar–capillary membrane as occurs with structure (black arrows). The white arrow points to the edge of an aspiration and many forms of infectious pneumonitis (Figure 11). adjacent alveolus, which contains myeloid leukocytes. The recent studies of complement activation, specifically generation C. An electron micrograph from a classic analysis of ALI/ARDS showing of C5a, and consequent activation of PMNs contributed a new facet injury to the capillary endothelium and the alveolar epithelium. LC refers to concepts of the pathogenesis of ALI/ARDS. Together with reports to a leukocyte (a neutrophil) within the capillary lumen. EC designates demonstrating endothelial injury by PMN proteases and oxidants, erythrocytes. EN shows blebbing of the capillary endothelium. BM these observations provided a conceptual model in which generation refers to exposed basement membrane where the epithelium has been of a circulating mediator (in this case, C5a) induces systemic activation denuded. C refers to the capillary. A refers to the alveolar space. of PMNs, resulting in aggregation and sequestration in pulmonary Additional analyses of leukocytes in the blood and alveoli of microvessels and consequent diffuse lung injury. This suggested a subjects with ALI/ARDS indicated that accumulation and activation mechanism by which indirect alveolar–capillary membrane injury of PMNs could not be completely explained by existing information’s is caused, as in systemic sepsis and non-thoracic trauma. Leukocyte and known mediators such as C5a, and stimulated new investigators activation leading to intravascular sequestration, alone or involving in the field to develop alternative models and hypotheses and to draw interacting platelets is consistent with findings in much more recent on previous and parallel investigations of inflammatory pathways in studies of the pathophysiology of ALI/ARDS. These concepts of other systems. One outcome was identification of endothelial cell PMN activation and aggregation also contributed to early suggestions activation as a mechanism of leukocyte accumulation and signaling. that glucocorticoids, inhibitors of PMN granular proteases, and Thus, key mediators might not be acting directly on the leukocytes but antioxidants might be specific therapeutic agen agents [a potential instead on the lung endothelium, resulting in accumulation of PMNs, that, although mechanistically based, has not subsequently been inflammatory injury, and, potentially, accumulation of other leukocyte realized] (Figure 13). types in the injured lung. A key concept in current pathobiology is that endothelial activation is central to inflammation in the lung

Citation: Zwer F. Acute lung injury & acute respiratory distress syndrome - part I. J Anesth Crit Care Open Access. 2015;3(5):11‒12. DOI: 10.15406/jaccoa.2015.03.00109 Copyright: Acute lung injury & acute respiratory distress syndrome - part I ©2015 Zwer 22 and elsewhere.30 Subsequent studies have examined mechanisms factors and the pattern of ventilation induce or amplify alveolar that regulate leukocyte–endothelial interactions in the pulmonary inflammation and injury and contribute to nonpulmonary organ injury. versus systemic circulations, where there are both differences and Thus, unfavorable ventilation strategies can compound the severity of similarities. These issues have additional complexity because ALI/ ALI, adding an iatrogenic variable to classic triggers of injury. Oxygen ARDS can involve both pulmonary and systemic vascular beds. in high concentrations, which is vital in the support of patients with ALI/ARDS, can also be toxic to alveolar–capillary membrane cells of animals and humans and presents another mechanism of iatrogenic injury, although one recent clinical trial found no decrease in mortality when a lower fraction of inspired oxygen was used in patients with higher levels of positive endexpiratory pressure. In animal models, hyperoxia increases intrapulmonary retention of PMNs and induces dysregulation of other innate immune mechanisms. Inflammatory cytokines can worsen or, conversely, ameliorate oxygen injury in surrogate models (Figure 14). βThe concept of ALI mediated by PMNs and circulating or locally generated mediators (Figure 13) with origins outlined above, continues to be central to current concepts of the pathogenesis of ALI/ARDS and has been emphasized in reviews and symposia that span two decades. Inflammation was identified as a key feature in the 1994 Consensus conference on ALI/ARDS. The concept has also evolved in complexity and detail. C5a, which remains topical but is not a final common pathway to ALI/ARDS, is now complemented by chemokines, cytokines, and lipid signaling molecules. PMNs are themselves sources of some of these factors. In some cases, identification of individual inflammatory mediators in cell biologic and preclinical models has generated candidate therapeutic Figure 13 Multiple cellular responses and mediators contribute to alveolar– strategies that have been tested in clinical trials. Intracellular signaling capillary membrane injury (right hand side) and the transition from normal pathways that link PMN surface receptors to activation responses, alveolar structure and function (left-hand side) in the acute phase of ALI/ including kinases and the NF-κB family of transcription factors, are ARDS. Original investigations of the pathogenesis of ALI/ARDS searched implicated as potential points of intervention, and it is recognized for single mediators that provided final common pathways to inflammation that these pathways are modulated by surface integrins, selectins, and and alveolar Edema in ALI/ARDS. Current concepts of pathogenesis involve multiple molecular factors of several classes, a variety of responding cells, and selectin ligands, which are adhesion molecules that also mediate tissue imbalance between injurious and reparative signals and pathways. See text for accumulation of leukocytes. PMN activities besides acute generation more details. of oxidants and release of proteases, such as signaling of endothelium, inflammatory gene expression and apoptosis are believed tobe relevant. There is evidence that injurious versus protective responses of PMNs may influence outcomes and that there are time-dependent changes in PMN number and phenotype in ALI/ARDS, although the significance of these findings remains incompletely explored. It also seems unlikely that PMNs act alone in any of the phases of ALI/ ARDS (Figure 13), although they may have particular roles at acute and subacute time points. Lung macrophages, circulating monocyte subpopulations, and other leukocyte subtypes have been suggested as key effector cells and have been considered in a preliminary fashion Figure 14 The natural history of ALI/ARDS includes resolution and repair versus persistence and progression. Clinical and epidemiologic studies in both early and later studies, although little functional data exist. demonstrate that ALI/ARDS resolves with return of alveolar function to normal The roles of platelets, which were detected in the acutely injured or near normal in some patients, whereas in others there is persistence and/ lung in early studies and molecular and cellular links between the or progression of injury. The outcomes of persistence and progression include thrombotic and inflammatory systems, remain topical issues. This multiple organ failure, fibrosing alveolitis, pulmonary vascular obliteration is in part because of the potential therapeutic use of recombinant with pulmonary hypertension, and death. The genetic, cellular, molecular and activated protein C (APC) in sepsis, a key triggering conditions for iatrogenic factors that contribute to each of these outcomes remain largely ALI/ARDS. APC interrupts both inflammatory and thrombotic events unknown. In addition, rational mechanism-based strategies that favorably in experimental studies. Platelets release IL-1 influence repair of the alveolar–capillary membrane are undefined. Resolution of lung injury: The natural history of ALI/ARDS has HMBG-1, and chemokines and also directly interact with PMNs been progressively defined by clinical studies and follows a variable and monocytes in addition to organizing fibrin clots; thus, they are course. One outcome is resolution and repair (Figure 14). The active in innate immune cascades and may modify inflammatory successful resolution of pulmonary edema and lung inflammation injury in ALI/ARDS. In parallel, however, platelets also release is an important determinant of recovery from acute lung injury. sphingosine-1-phosphate, which promotes endothelial barrier Early studies demonstrated that lung lymphatics and the pulmonary function in experimental models. This illustrates the well known fact microcirculation remove edema fluid from the interstitium of the that platelets have both defensive and reparative activities. Thus, it is lung and that fluid flow into the pleural space is an additional major not yet clear if their accumulation and activation in the lungs has a pathway for edema translocation. A new mechanism was recognized net positive or negative effect on the outcome of ALI/ARDS. Also, in in the 1980s when investigators demonstrated that removal of alveolar addition the animal and human studies demonstrate that mechanical edema fluid depends on orientation transport of salt and water across

Citation: Zwer F. Acute lung injury & acute respiratory distress syndrome - part I. J Anesth Crit Care Open Access. 2015;3(5):11‒12. DOI: 10.15406/jaccoa.2015.03.00109 Copyright: Acute lung injury & acute respiratory distress syndrome - part I ©2015 Zwer 23 the alveolar epithelium in part through apical located epithelial sodium and insoluble proteins are removed from the lung. Characterizations of channels (ENaC), followed by extrusion into the lung interstitium via molecular mechanisms that regulate macrophage-dependent removal a basolaterally located Na-KATPase (Figure 15). The transport of of apoptotic leukocytes in inflammatory lung injury are in progress. sodium creates a mini– osmotic gradient that absorbs water from the Soluble protein appears to be primarily removed by a slow process airspaces via water channels (aquaporins) and paracellular pathways.31 of paracellular diffusion across the alveolar epithelium although Net alveolar fluid clearance can be upregulated by cAMP agonists in transcytosis can contribute as well. Removal of insoluble proteins and many species, including the human lung. Recent evidence suggests cellular debris and remodeling of hyaline membranes appears to be that the cystic fibrosis chloride channel, CFTR, is required for effective primarily driven by alveolar macrophages. cAMP stimulated fluid transport. Both alveolar type II and typeI Where we are now: In spite of elements of progress, much remains cells may be capable of driving sodium transport and net alveolar to be learned. This was apparent to an interdisciplinary group of fluid clearance. The transport capacity of the alveolar epithelium is investigators that met to discuss the state of the field and future markedly diminished in ALI, a finding that correlates with higher research priorities in ALI/ARDS in 2002. The issues are broad and the mortality. The mechanisms for the decrease in alveolar fluid clearance unknown’s complex. However, in all of the facets of the inflammatory include frank injury to alveolar epithelial cells and their apoptosis or and haemostatic responses in ALI/ARDS (Figures 11 & , a regulatory necrosis, resulting in loss of barrier and transport properties as well as cytokine, has important activities that modulate inflammation more subtle defects in ion transport capacity. Oxidant injury, reactive and edema, but recent evidence suggests that it may also enhance nitrogen species, hypoxia, and direct effects of bacterial and viral endothelial and epithelial permeability and have a net deleterious pathogens alter the transport machinery in theepithelial cells, as do effect in the acutely injured lung.β13) we still have little insight into unfavorable ventilatory strategies (Figure 15). what is cause and what is consequence. Although some progress has been made, we are little closer than we were in 1967 to understanding how key inflammatory events that are defensive and reparative when they are regulated in lung infection and limited injury become damaging and destructive when they are unregulated in ALI/ARDS, and we have very little insight into what the molecular mechanisms of dysregulation actually are. In bacterial pneumonia, innate immune responses mediated by activated neutrophils, monocytes, and alveolar macrophages play requisite roles. In parallel, a local shift to a pro- coagulant and antifibrinolytic environment may serve to wall off infection and airspace injury, yet these same effectors and responses appear to be essential in the early events in ALI/ARDS (Figure 11). The concept of a balance between pro- and anti-inflammatory and pro- and anti-edematous factors has current traction in the field, in part borrowed from other diseases and mechanisms of injury. Further, specific regulatory molecules may have essential activities that usually Figure 15 Cellular and molecular pathways regulate the resolution of keep lung inflammation and edema in check. Nevertheless, while the alveolar edema formation and resolution in ALI/ARDS. Histologic section concepts are objecting, the defining mechanisms remain obscure from patients with a lung biopsy in the setting of lung injury from bacterial and many molecular factors may play some effect. As an example, pneumonia and sepsis with protein rich alveolar edema. The insert refers to transforming growth factor. ENaC, the epithelial sodium channel, which is a major pathway for the uptake of sodium on the apical surface of alveolar epithelial type I and II cells as well The drive to understand initiation of ALI, the acute inflammatory as distal airway epithelia. NaKATPase refers to the sodium pump located in components of ALI/ARDS, and their resolution (Figure 11) has been the basolateral surface of alveolar and airway epithelia that actively pumps accompanied by focused intent to define cellular and molecular sodium into the interstitial space, thus creating a mini–osmotic gradient for events that contribute to progressive alveolar–capillary injury and the absorption of edema fluid from the alveolar. Both ENaC and NaKATPase can be up regulated by several catecholamine dependent and independent dysregulated repair (Figure 14), particularly in the last decade of mechanisms. molecular medicine. It is clear from clinical and epidemiologic studies that specific biologic features prevent the resolution of ALI More precise understanding of how the alveolar endothelium and in some subjects, resulting in persistence and progression to severe epithelium interact, and their coordinate responses to inflammatory complications including multiple organ failure, fibrosing alveolitis, cells and cytokines, could clarify mechanisms by which lung and alveolar endothelial and epithelial cell destruction (Figures 12 & endothelial injury leads to alveolar edema (Figure 11) and how 14). The understanding here is extremely limited. Further progress will resolution of edema is modulated (Figures 14 & 15). Experimentally, likely require more cell biologic experiments and models to establish alveolar endothelial injury from endotoxin can occur without molecular effects that can then be explored in animal models and, accumulation of alveolar edema, apparently because epithelial injury ultimately, in critically ill patients. In addition, genetic determinants is mild. In contrast, substitution of live pathogenic bacteria results of these responses and how they vary among individuals and interact in both endothelial and epithelial injury. Since direct or indirect with environmental influences are not largely explored. Cellular, infection accounts for more than 60% of clinical cases of ALI in genomic, proteomic, and lipidomic patterns in the acutely injured most studies, a better understanding of how the bacterial and viral lung and in lungs undergoing regulated repair versus dysregulated products alter these and other aspects of alveolar–capillary function is progression remain to be defined. Thus, the biologic basis required for critical. Furthermore, it is essential to determine how well the alveolar clear understanding of the natural history of ALI/ARDS and for new epithelium recovers from apoptotic or necrotic lung injury and the basic strategies for intervention remains incompletely defined. Finally, the mechanisms that regulate this process of epithelial repair. It is also success of a lung protective ventilatory strategy in reducing mortality critical to understand more about how inflammatory cells and soluble in ALI/ARDS is a good example of how clinical trials are needed

8. Britos M, Smoot E, Liu KD, et al. The value of PEEP and FiO2 criteria for acute lung injury in the intensive care unit and hospital ward: a in the definition the acute respiratory distress syndrome.Crit Care Med. prospective observational study. Critical Care. 2007;11(5):R96. 2011;39(9):2025–2030. 29. Trillo–Alvarez C, Cartin–Ceba R, Kor DJ, et al. Acute lung injury 9. Moss M, Goodman PL, Heinig M, et al. Establishing the relative prediction score: derivation and validation in a population based sample. accuracy of three new definitions of the adult respiratory distress Eur Respir J. 2011;37(3):604–609. syndrome. Crit Care Med. 1995;23(10):1629–1637. 30. Ward PA, Hunninghake GW. Lung inflammation and fibrosis. Am J 10. Goh AYT, Chan PWK, Lum LCS, et al. Incidence of acute respiratory Respir Crit Care Med. 1998;157(4 Pt 2): S123–S129. distress syndrome: a comparison of two definitions. Arch Dis Child. 1998;79(3):256–259. 31. Matthay MA, Zimmerman GA. Acute lung injury and the acute respiratory distress syndrome: four decades of inquiry into pathogenesis 11. Villar J, Kacmarek RM. The American–European Consensus Conference and rational management. Am J Respir Cell Mol Biol. 2005;33(4):319– definition of the acute respiratory distress syndrome is dead, long live 327. positive end–expiratory pressure! Med Intensiva. 2012;36(8):571–575.

32. Matthay MA, Folkesson HG, Clerici C. Lung epithelial fluid transport 33. Ranieri VM, Rubenfeld GD, Thompson BT, et al. The ARDS and the resolution of pulmonary edema. Physiol Rev. 2002;82(3):569– Definition Task Force. Acute respiratory distress syndrome. JAMA. 600. 2012;307(23):2526–2533.

Citation: Zwer F. Acute lung injury & acute respiratory distress syndrome - part I. J Anesth Crit Care Open Access. 2015;3(5):11‒12. DOI: 10.15406/jaccoa.2015.03.00109